Hemp extract for treatment of pain in animals

ABSTRACT

The present disclosure relates to methods of treating pain in veterinary subjects using pharmaceutical compositions and dosage forms comprising hemp extract. In an aspect, provided herein is a pharmaceutical composition comprising hemp extract and a carrier, wherein the hemp extract comprises cannabidiol; and cannabidiolic acid; wherein the ratio of cannabidiol to cannabidiolic acid is about 0.6:1 to about 1:0.6.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 62/655,170, filed Apr. 9, 2018, the entiredisclosure of which is hereby incorporated herein by reference.

BACKGROUND

Routine nonsteroidal anti-inflammatory drug (NSAID) treatments, thoughefficacious, may not provide adequate relief of pain due toosteoarthritis (OA) and might have potential side effects that precludeits use, particularly in patients with certain comorbidities. In asystematic review of 35 canine models of OA and 29 clinical trials indogs, treatment with NSAIDs caused adverse effects in 35 of the 64 (55%)studies, most common being gastro-intestinal signs. Although otherpharmacological agents are advocated, there is little evidence regardingtheir efficacy in dogs with chronic or neuropathic pain related to OA.In the absence of an optimal treatment for these dogs, other potentiallyefficacious pharmacological agents, including cannabinoids, are oftensought.

SUMMARY

The present disclosure is directed toward compositions comprisingcannabidiol and their use for the treatment of pain in animals. In anaspect, provided herein is a pharmaceutical composition comprising hempextract and a carrier, wherein the hemp extract comprises:

cannabidiol;

cannabidiolic acid;

cannabigerolic acid;

Δ9-tetrahydrocannabinol; and

cannabichromene;

wherein the ratio of cannabidiol to cannabidiolic acid is about 0.6:1 toabout 1:0.6.

In an embodiment, the hemp extract further comprises four or more of thefollowing:

α-pinene;

β-myrcene;

β-pinene;

δ-limonene;

linalool;

β-caryophyllene;

α-humulene;

nerolidol 2;

guaiol;

caryophyllene oxide; and

α-bisabolol.

In an embodiment, the concentration of Δ9-tetrahydrocannabinol isinsufficient to produce a psychotropic effect. In an embodiment, theratio of Δ9-tetrahydrocannabinol to the other cannabinoids is about1:25. In another embodiment, the concentration of Δ9tetrahydrocannabinol is less than about 1 mg/mL. In another embodiment,the concentration of Δ9-tetrahydrocannabinol is less than about 0.5mg/mL. In another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.3 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.2 mg/mL. In another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.1 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.

In an embodiment, the ratio of cannabidiol to cannabidiolic acid isselected from the group consisting of about 1:100, about 1:50, about1:10, and about 1:1. In another embodiment, the ratio of cannabidiol tocannabidiolic acid is about 1:1.

In an embodiment, the hemp extract comprises:

about 1-10 mg/mL of cannabidiol;

about 1-10 mg/mL of cannabidiolic acid;

about 0.05-0.2 mg/mL cannabigerolic acid;

about 0.1-0.3 mg/mL Δ9-tetrahydrocannabinol; and

about 0.1-0.4 mg/mL cannabichromene.

In another embodiment, the hemp extract comprises:

about 5 mg/mL of cannabidiol;

about 5 mg/mL of cannabidiolic acid;

about 0.11 mg/mL cannabigerolic acid;

about 0.25 mg/mL Δ9-tetrahydrocannabinol; and

about 0.27 mg/mL cannabichromene.

In another embodiment, the hemp extract comprises:

about 0.09-0.13% α-pinene;

about 0.23-0.44% β-myrcene;

about 0.04-0.09% β-pinene;

about 0.05-0.09% δ-limonene;

about 0.03-0.06% linalool;

about 0.04-0.07% β-caryophyllene;

about 0.02-0.04% α-humulene;

about 0.04-0.07% nerolidol 2;

about 0.02-0.04% guaiol;

about 0.04-0.08% caryophyllene oxide; and

about 0.01-0.04% α-bisabolol.

In another embodiment, the hemp extract further comprises:

camphene;

β-ocimene;

eucalyptol;

isopulegol; and/or

nerolidol 1.

In another embodiment, the hemp extract comprises:

about 0.02% camphene;

about 0.02-0.03% β-ocimene;

about 0.02-0.05% eucalyptol;

about 0.02% isopulegol; and/or

about 0.02-0.04% nerolidol 1.

In an embodiment, the hemp extract comprises 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15 or more of the following: α-pinene, β-myrcene, β-pinene,δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol,caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol,isopulegol, and nerolidol 1.

In an embodiment, the composition is formulated in a carrier. In anotherembodiment, the carrier is selected from the group consisting of linseedoil, olive oil, fish oil, salmon oil, coconut oil, catnip oil, andgrapeseed oil. In another embodiment, the carrier is grapeseed oil. Inanother embodiment, the carrier is catnip oil. In another embodiment,the composition comprises nepetalactone. In another embodiment, whereinthe composition comprises taurine.

In an embodiment, the hemp extract comprises:

cannabidiol;

cannabidiolic acid;

cannabigerolic acid;

Δ9-tetrahydrocannabinol; and

cannabichromene;

wherein the carrier is grapeseed oil.

In an embodiment, the composition is formulated for administration usinga nebulizer. In another embodiment, the composition is formulated foradministration using a diffuser. In another embodiment, the compositionis formulated for administration using a pet collar. In anotherembodiment, the composition is formulated as a pet food for oraladministration.

In an embodiment, the composition is formulated as a chew for oraladministration. In another embodiment, the weight of the chew is about0.5-10 g. In another embodiment, the weight of the chew is about 4 g,about 6 g, about 9 g, or about 10 g. In another embodiment, the weightof the chew is about 4 g.

In another embodiment, the chew comprises:

about 7 mg of cannabidiol;

about 6 mg of cannabidiolic acid;

about 0.12 mg cannabigerolic acid;

about 0.32 mg Δ9-tetrahydrocannabinol; and

about 0.36 mg cannabichromene.

In an embodiment, a dosage form comprises:

cannabidiol;

cannabidiolic acid;

cannabigerolic acid;

Δ9-tetrahydrocannabinol;

cannabichromene; and

one or more pharmaceutically acceptable additives, flavoring agents,surfactants, and adjuvants.

In another embodiment, the dosage form comprises:

about 1-10 mg/mL of cannabidiol;

about 1-10 mg/mL of cannabidiolic acid;

about 0.05-0.2 mg/mL cannabigerolic acid;

about 0.1-0.3 mg/mL Δ9-tetrahydrocannabinol; and

about 0.1-0.4 mg/mL cannabichromene.

In another embodiment, the dosage form comprises:

about 5 mg/mL of cannabidiol;

about 5 mg/mL of cannabidiolic acid;

about 0.11 mg/mL cannabigerolic acid;

about 0.25 mg/mL Δ9-tetrahydrocannabinol; and

about 0.27 mg/mL cannabichromene.

In an embodiment, the dosage form comprises:

α-pinene;

β-myrcene;

β-pinene;

δ-limonene;

linalool;

β-caryophyllene;

α-humulene;

nerolidol 2;

guaiol;

caryophyllene oxide; and

α-bisabolol.

In another embodiment, the dosage form comprises:

about 0.09-0.13% α-pinene;

about 0.23-0.44% β-myrcene;

about 0.04-0.09% β-pinene;

about 0.05-0.09% δ-limonene;

about 0.03-0.06% linalool;

about 0.04-0.07% β-caryophyllene;

about 0.02-0.04% α-humulene;

about 0.04-0.07% nerolidol 2;

about 0.02-0.04% guaiol;

about 0.04-0.08% caryophyllene oxide; and

about 0.01-0.04% α-bisabolol.

In another embodiment, the dosage form further comprises:

camphene;

β-ocimene;

eucalyptol;

isopulegol; and/or

nerolidol 1.

In another embodiment, the dosage form comprises:

about 0.02% camphene;

about 0.02-0.03% β-ocimene;

about 0.02-0.05% eucalyptol;

about 0.02% isopulegol; and/or

about 0.02-0.04% nerolidol 1.

In another embodiment, the dosage form comprises 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15 or more of the following: α-pinene, β-myrcene, β-pinene,δ-limonene, linalool, β-caryophyllene, α-humulene, nerolidol 2, guaiol,caryophyllene oxide, α-bisabolol, camphene, β-ocimene, eucalyptol,isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises a flavoring agent selectedfrom the group consisting of catnip oil, peppermint oil, mango extract,beef, poultry, and seafood. In an embodiment, the flavoring agent iscatnip oil. In an embodiment, the flavoring agent is selected from thegroup consisting of catnip oil, chicken liver powder, poultry extract,maltodextrin, butter, and bacon. In an embodiment, the flavoring agentis chicken liver powder.

In an embodiment, the dosage form comprises nepetalactone. In anembodiment, the dosage form comprises taurine.

In an embodiment, the dosage form is formulated as a chew for oraladministration. In an embodiment, the chew is produced using coldextrusion. In another embodiment, the dosage form is formulated as asublingual spray. In another embodiment, the dosage form is formulatedas a water or alcohol soluble solution, a gel, or a cream fortransdermal application. In another embodiment, the dosage form isformulated as a gel for buccal or mucosal administration. In anotherembodiment, the dosage form is formulated as a powder. In anotherembodiment, the dosage form is formulated as a solution for subcutaneousinjection. In another embodiment, the dosage form is formulated as atablet. In another embodiment, the dosage form is formulated as acapsule. In another embodiment, the dosage form is formulated as a hardchewable. In another embodiment, the dosage form is formulated forinhalation. In another embodiment, the dosage form is formulated foradministration using a nebulizer. In another embodiment, the dosage formis formulated for administration using a diffuser. In anotherembodiment, the dosage form is formulated for administration using a petcollar.

In an embodiment, the dosage form is formulated in a carrier for oraladministration. In an embodiment, the carrier is selected from the groupconsisting of linseed oil, olive oil, fish oil, salmon oil, coconut oil,catnip oil, and grapeseed oil. In another embodiment, the carrier isgrapeseed oil. In another embodiment, the carrier is catnip oil.

In an embodiment, a dosage form comprises:

glucosamine HCl;

chondroitin sulfate (76%);

brewer's yeast;

arabic gum;

guar gum;

a flavoring agent;

Verdilox;

Previon;

hemp extract;

glycerin;

sunflower lecithin; and

water.

In another embodiment, the dosage form comprises:

about 12-17% glucosamine HCl;

about 1-4% chondroitin sulfate (76%);

about 29-33% brewer's yeast;

about 3-6% arabic gum;

about 0.5-2% guar gum;

about 12-16% of a flavoring agent;

about 0.01-0.1% Verdilox;

about 0.5-1.5% Previon;

about 3-6% hemp extract;

about 13-17% glycerin;

about 3-7% sunflower lecithin; and

about 3-7% water.

In another embodiment, the dosage form comprises:

about 15.6% glucosamine HCl;

about 2.6% chondroitin sulfate (76%);

about 30% brewer's yeast;

about 4.7% arabic gum;

about 0.9% guar gum;

about 14.2% of a flavoring agent;

about 0.05% Verdilox;

about 0.9% Previon;

about 4.7% hemp extract;

about 15.1% glycerin;

about 5.7% sunflower lecithin; and

about 5.7% water.

In an embodiment, a dosage form comprises:

glucosamine HCl;

hyaluronic acid;

brewer's yeast;

arabic gum;

guar gum;

a flavoring agent;

Verdilox;

Previon;

hemp extract;

glycerin;

sunflower lecithin; and

water.

In another embodiment, the dosage form comprises:

about 12-17% glucosamine HCl;

about 0.01-1% hyaluronic acid;

about 29-33% brewer's yeast;

about 3-6% arabic gum;

about 0.5-2% guar gum;

about 12-16% of a flavoring agent;

about 0.01-0.1% Verdilox;

about 0.5-1.5% Previon;

about 3-6% hemp extract;

about 13-17% glycerin;

about 3-7% sunflower lecithin; and

about 3-7% water.

In another embodiment, the dosage form comprises:

about 16% glucosamine HCl;

about 0.1% hyaluronic acid;

about 30.6% brewer's yeast;

about 4.8% arabic gum;

about 0.97% guar gum;

about 14.5% of a flavoring agent;

about 0.05% Verdilox;

about 0.97% Previon;

about 4.8% hemp extract;

about 15.5% glycerin;

about 5.8% sunflower lecithin; and

about 5.8% water.

In an embodiment, a dosage form comprises:

hemp extract;

peanut butter;

rice bran;

glucosamine HCL;

sweet potato;

dry molasses;

sorbic acid

brewer's yeast;

sugar;

water;

glycerin;

potato starch;

dehydrated peanut butter;

rice starch; and

guar gum.

In another embodiment, the dosage form comprises:

about 5.0% hemp extract;

about 15.0% peanut butter;

about 12.5% rice bran;

about 12.75% glucosamine HCL;

about 5.5% sweet potato;

about 8.0% dry molasses;

about 1% sorbic acid;

about 5.0% brewer's yeast;

about 6.0% sugar;

about 9.25% water;

about 13.0 glycerin;

about 2.0% potato starch;

about 1.0% dehydrated peanut butter;

about 2.0% rice starch; and

about 2.0% guar gum.

In another embodiment, the dosage form comprises:

about 5.0% hemp extract;

about 15.0% peanut butter;

about 13.0% rice bran;

about 8.5% glucosamine HCL;

about 6.0% sweet potato;

about 9.0% dry molasses;

about 1% sorbic acid;

about 5.0% brewer's yeast;

about 6.0% sugar;

about 9.5% water;

about 13.0 glycerin;

about 4.0% potato starch;

about 1.0% dehydrated peanut butter;

about 2.0% rice starch; and

about 2.0% guar gum.

In another embodiment, the dosage form comprises:

about 3.0-10.0% hemp extract;

about 10.0-20.0% peanut butter;

about 10.0-15.0% rice bran;

about 5.0-15.0% glucosamine HCL;

about 4.0-10.0% sweet potato;

about 6.0-13.0% dry molasses;

about 0.5-5.0% sorbic acid;

about 2.0-8.0% brewer's yeast;

about 3.0-8.0% sugar;

about 5.0-15.0% water;

about 8.0-18.0% glycerin;

about 1.0-8.0% potato starch;

about 0.5-5.0% dehydrated peanut butter;

about 1.0-5.0% rice starch; and

about 1.0-5.0% guar gum.

In an aspect, provided herein is a method for treating or reducing painin a veterinary subject in need thereof, comprising administering to thesubject a therapeutically effective amount of the compositions or adosage forms described above. In an embodiment, the pain is associatedwith arthritis, post-operative pain, acute pain, dental pain, painassociated with gingivitis, or multi-joint pain.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1.0 mg/kg twice daily. In anotherembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1.0 mg/kg three times daily. Inanother embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2.0 mg/kg twice daily. In anotherembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2.0 mg/kg three times daily. Inanother embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 0.1-8.0 mg/kg.

In another embodiment, the pharmaceutical composition or dosage form isadministered at twice the therapeutically effective dosage for one week,and then subsequently administered at a therapeutically effectivedosage. In another embodiment, the therapeutically effective dosage isabout 0.1-0.5 mg/kg. In another embodiment, the therapeuticallyeffective dosage is about 2 mg/kg. In another embodiment, thetherapeutically effective dosage is about 8 mg/kg. In anotherembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1 mg/kg for one week, and thensubsequently administered at a dosage of about 0.1-0.5 mg/kg. In anotherembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 4 mg/kg for one week, and thensubsequently administered at a dosage of about 2 mg/kg.

In an embodiment, the method results in a therapeutically effectivemedian maximal serum concentration of cannabidiol. In an embodiment, themedian maximal serum concentration of cannabidiol is about 102 ng/mL. Inanother embodiment, the median maximal serum concentration ofcannabidiol is about 590 ng/mL.

In an aspect, provided herein is a method for treating or reducing painassociated with arthritis, post-operative pain, acute pain, dental pain,pain associated with gingivitis, or multi-joint pain in a veterinarysubject in need thereof, comprising administering to the subject atherapeutically effective amount of hemp extract.

In an embodiment, the hemp extract is administered at a dosage of about0.1-8.0 mg/kg. In another embodiment, the hemp extract is administeredat twice the therapeutically effective dosage for one week, and thensubsequently administered at a therapeutically effective dosage. Inanother embodiment, the therapeutically effective dosage is about0.1-0.5 mg/kg. In another embodiment, the therapeutically effectivedosage is about 1 mg/kg. In another embodiment, the therapeuticallyeffective dosage is about 2 mg/kg. In another embodiment, thetherapeutically effective dosage is about 8 mg/kg.

In an embodiment, the hemp extract is administered at a dosage of about1 mg/kg for one week, and then subsequently administered at a dosage ofabout 0.1-0.5 mg/kg. In another embodiment, the hemp extract isadministered at a dosage of about 4 mg/kg for one week, and thensubsequently administered at a dosage of about 2 mg/kg.

In an embodiment, the method results in a therapeutically effectivemedian maximal serum concentration of cannabidiol. In anotherembodiment, the median maximal serum concentration of cannabidiol isabout 102 ng/mL. In another embodiment, the median maximal serumconcentration of cannabidiol is about 590 ng/mL.

In an embodiment, the veterinary subject is canine, feline, bovine,porcine, or equine. In another embodiment, the veterinary subject iscanine. In another embodiment, the veterinary subject is feline.

In an aspect, provided herein is a method of achieving an area under thecurve from 0 time to 24 hours of between 42.4 and 3048 ng hr/ml forcannabidiol in a veterinary subject comprising administering to thesubject an effective amount of hemp extract. In an embodiment, thesubject is canine or feline.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 : Box-and-whisker plot of serum alkaline phosphatase (ALP)activity at each time for treatment and placebo oils. Box represents themean and 25th and 75th percentile and the whiskers represent the 99thand 1st percentiles.

FIG. 2 : Serum concentration (ng/mL) of 2 mg/kg and 8 mg/kg oral dosageof CBD oil in time (min)

FIG. 3A: Box-and-whisker plot of total CBPI score at each time fortreatment and placebo oils. Box represents the mean and 25th and 75thpercentile and the whiskers represent the 99th and 1st percentiles.

FIG. 3B: Box-and-whisker plot of total Hudson score at each time fortreatment and placebo oils. Box represents the mean and 25th and 75thpercentile and the whiskers represent the 99th and 1st percentiles.

FIG. 4 : Box-and-whisker plot of total vet pain assessment at each timefor treatment and placebo oils.

FIGS. 5A-5F: Graphs showing trot stance % gait cycle symmetry (FIG. 5A),trot stance % gait cycle (FIG. 5B), trot step/stride ratio (FIG. 5C),walk stance % gait cycle symmetry (FIG. 5D), walk stance % gait cycle(FIG. 5E), and walk step/stride ratio (FIG. 5F) for five dogs treatedwith CBD.

DETAILED DESCRIPTION

The endocannabinoid receptor system is known to play a role in painmodulation and attenuation of inflammation. Cannabinoid receptors (CB1and CB2) are widely distributed throughout the central and peripheralnervous system and are also present in the synovium. However, thepsychotropic effects of certain cannabinoids prevent extensive researchinto their use as single agents for pain relief. The cannabinoids are agroup of as many as 60 different compounds that may or may not act at CBreceptors. One class of cannabinoids, cannabidiol (CBD), may actually bean antagonist of the CB receptors. In lower vertebrates, CBD can alsohave immunomodulatory, anti-hyperalgesic, antinociceptive, andanti-inflammatory actions, making it an attractive therapeutic option indogs with OA.

The present disclosure is directed toward compositions comprising hempextract and their use for the treatment of pain in animals. Alsoprovided herein are methods for treatment of pain in veterinarysubjects. The efficacy of these compositions and treatment methods hasnot previously been demonstrated. Clinical trial and pharmacokineticdata regarding dosing is also provided herein.

Definitions

Listed below are definitions of various terms used herein. Thesedefinitions apply to the terms as they are used throughout thisspecification and claims, unless otherwise limited in specificinstances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Generally,the nomenclature used herein and the laboratory procedures in cellculture, molecular genetics, organic chemistry, and peptide chemistryare those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more thanone (i.e., to at least one) of the grammatical object of the article. Byway of example, “an element” means one element or more than one element.Furthermore, use of the term “including” as well as other forms, such as“include,” “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent on the context inwhich it is used. As used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, the term “about”is meant to encompass variations of ±5%, from the specified value, assuch variations are appropriate to perform the disclosed methods.

As used in the specification and in the claims, the term “comprising”may include the embodiments “consisting of” and “consisting essentiallyof.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,”“contain(s),” and variants thereof, as used herein, are intended to beopen-ended transitional phrases, terms, or words that require thepresence of the named ingredients/steps and permit the presence of otheringredients/steps. However, such description should be construed as alsodescribing compositions or processes as “consisting of” and “consistingessentially of” the enumerated compounds, which allows the presence ofonly the named compounds, along with any pharmaceutically acceptablecarriers, and excludes other compounds.

All ranges disclosed herein are inclusive of the recited endpoint andindependently combinable (for example, the range of “from 50 mg to 500mg” is inclusive of the endpoints, 50 mg and 500 mg, and all theintermediate values). The endpoints of the ranges and any valuesdisclosed herein are not limited to the precise range or value; they aresufficiently imprecise to include values approximating these rangesand/or values.

As used herein, the term “treatment” or “treating,” is defined as theapplication or administration of a therapeutic agent, i.e., a compoundprovided herein (alone or in combination with another pharmaceuticalagent), to a patient, or application or administration of a therapeuticagent to an isolated tissue or cell line from a patient (e.g., fordiagnosis or ex vivo applications), with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thesymptoms of a disease, disorder, syndrome, or condition. Such treatmentscan be specifically tailored or modified, based on knowledge obtainedfrom the field of pharmacogenomics.

In certain embodiments, the compositions described herein reduce pain ina subject. Pain can be measured using any metric known in the art. Forexample, pain can be measured using the canine brief pain inventory(CBPI), the Hudson activity scale, flexion and tension measurements andgait analysis. A reduction in any of these metrics shows a treatment ofor reduction in pain.

As used herein, the term “prevent” or “prevention” means no disorder ordisease development if none had occurred, or no further disorder ordisease development if there had already been development of thedisorder or disease. Also considered is the ability of one to preventsome or all of the symptoms associated with the disorder or disease.

As used herein, the term “use” includes any one or more of the followingembodiments of the invention, respectively: the use in the treatment ofpain the use for the manufacture of pharmaceutical compositions for usein the treatment of these diseases, e.g., in the manufacture of amedicament; methods of use of compounds of the invention in thetreatment of these diseases; pharmaceutical preparations havingcompounds of the invention for the treatment of these diseases; andcompounds of the invention for use in the treatment of these diseases;as appropriate and expedient, if not stated otherwise.

As used herein, the term “patient,” “individual,” or “subject” isintended to include organisms, e.g., prokaryotes and eukaryotes, whichare capable of suffering from or afflicted with a disease, disorder orcondition associated with the activity of a protein kinase. Examples ofsubjects include mammals, e.g., humans, dogs, cows, horses, pigs, sheep,goats, cats, mice, rabbits, rats, and transgenic non-human animals. Incertain embodiments, the subject is a human, e.g., a human sufferingfrom, at risk of suffering from, or potentially capable of sufferingfrom, schizophrenia. In another embodiment, the subject is a cell.

When used with respect to methods of treatment/prevention and the use ofthe compounds and pharmaceutical compositions thereof described herein,an individual “in need thereof” may be an individual who has beendiagnosed with or previously treated for the condition to be treated.With respect to prevention, the individual in need thereof may also bean individual who is at risk for a condition (e.g., a family history ofthe condition, life-style factors indicative of risk for the condition,etc.). Typically, when a step of administering a compound of theinvention is disclosed herein, the invention further contemplates a stepof identifying an individual or subject in need of the particulartreatment to be administered or having the particular condition to betreated.

In some embodiments, the individual is a mammal, including, but notlimited to, bovine, equine, feline, rabbit, canine, rodent, or primate.In some embodiments, the mammal is a primate. In some embodiments, theprimate is a human. In some embodiments, the individual is human,including adults, children and premature infants. In some embodiments,the individual is a non-mammal. In some variations, the primate is anon-human primate such as chimpanzees and other apes and monkey species.The term “individual” does not denote a particular age or sex.

As used herein, the term “pharmaceutically acceptable” refers to amaterial, such as a carrier or diluent, which does not abrogate thebiological activity or properties of the compound, and is relativelynon-toxic, i.e., the material can be administered to an individualwithout causing undesirable biological effects or interacting in adeleterious manner with any of the components of the composition inwhich it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by converting an existing acid or base moiety to its salt form.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts of thepresent invention include the conventional non-toxic salts of the parentcompound formed, for example, from non-toxic inorganic or organic acids.The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition”refers to a mixture of at least one compound useful within the inventionwith a pharmaceutically acceptable carrier. The pharmaceuticalcomposition facilitates administration of the compound to a patient orsubject. Multiple techniques of administering a compound exist in theart including, but not limited to, intravenous, oral, aerosol,parenteral, ophthalmic, pulmonary and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” or“carrier” means a pharmaceutically acceptable material, composition orcarrier, such as a liquid or solid filler, stabilizer, dispersing agent,suspending agent, diluent, excipient, thickening agent, solvent orencapsulating material, involved in carrying or transporting a compounduseful within the invention within or to the patient such that it canperform its intended function. Typically, such constructs are carried ortransported from one organ, or portion of the body, to another organ, orportion of the body. Each carrier must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation,including the compound useful within the invention, and not injurious tothe patient. Some examples of materials that can serve aspharmaceutically acceptable carriers include: sugars, such as lactose,glucose and sucrose; starches, such as corn starch and potato starch;cellulose, and its derivatives, such as sodium carboxymethyl cellulose,ethyl cellulose and cellulose acetate; powdered tragacanth; malt;gelatin; talc; excipients, such as cocoa butter and suppository waxes;oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil,olive oil, corn oil and soybean oil; glycols, such as propylene glycol;polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol;esters, such as ethyl oleate and ethyl laurate; agar; buffering agents,such as magnesium hydroxide and aluminum hydroxide; surface activeagents; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations. As usedherein, “pharmaceutically acceptable carrier” also includes any and allcoatings, antibacterial and antifungal agents, and absorption delayingagents, and the like that are compatible with the activity of thecompound useful within the invention, and are physiologically acceptableto the patient. Supplementary active compounds can also be incorporatedinto the compositions. The “pharmaceutically acceptable carrier” or“carrier” can further include a pharmaceutically acceptable salt of thecompound useful within the invention. Other additional ingredients thatcan be included in the pharmaceutical compositions used in the practiceof the invention are known in the art and described, for example inRemington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co.,1985, Easton, Pa.), which is incorporated herein by reference.

The term “stabilizer,” as used herein, refers to polymers capable ofchemically inhibiting or preventing degradation. Stabilizers are addedto formulations of compounds to improve chemical and physical stabilityof the compound.

As used herein, the term “adjuvant” may include, for example,preserving, wetting, suspending, sweetening, flavoring, perfuming,emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms is generally provided by various antibacterial andantifungal agents, such as, parabens, chlorobutanol, phenol, sorbicacid, and the like. Isotonic agents, such as sugars, sodium chloride,and the like, may also be included. Prolonged absorption of aninjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, for example, aluminum monostearate and gelatin. Theauxiliary agents also can include wetting agents, emulsifying agents, pHbuffering agents, and antioxidants, such as, for example, citric acid,sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene,and the like.

As used herein, the terms “effective amount,” “pharmaceuticallyeffective amount,” and “therapeutically effective amount” refer to anontoxic but sufficient amount of an agent to provide the desiredbiological result. That result may be reduction or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. An appropriate therapeutic amount in anyindividual case may be determined by one of ordinary skill in the artusing routine experimentation.

As used herein, the term “weight percent” is meant to refer to thequantity by weight of a compound and/or component in a composition asthe quantity by weight of a constituent component of the composition asa percentage of the weight of the total composition. The weight percentcan also be calculated by multiplying the mass fraction by 100. The“mass fraction” is the ratio of one substance of a mass m₁ to the massof the total composition m_(T) such that weight percent=(m₁/m_(T))*100.

“Aqueous buffer” refers to a water solution which resists change inhydronium ion and the hydroxide ion concentration (and consequent pH)upon addition of small amounts of acid or base, or upon dilution. Buffersolutions consist of a weak acid and its conjugate base (more common) ora weak base and its conjugate acid (less common). The buffer can beprepared by methods well known in the art with the appropriate bufferingagents to give the desired pH value. Examples of the suitable bufferingagents include hydrochloric acid, lactic acid, acetic acid, citric acid,malic acid, maleic acid, pyruvic acid, succinic acid,tris-hydroxymethylaminomethane, sodium hydroxide, sodium bicarbonate,phosphoric acid, sodium phosphate, and other biologically acceptablebuffering agents. Aqueous buffers are readily available commercially andthey can be used in preparation of the compositions of this inventionwithout further treatment.

As used herein, the term “hemp extract” refers to a composition ofcannabinoids and terpenes that are isolated from a hemp plant. The hempextract can be obtained by any method known in the art. For example, thehemp extract can be obtained by supercritical (or subcritical) CO₂extraction, which uses carbon dioxide under high pressure and lowtemperatures to isolate, preserve and maintain the purity of hempextract. In an embodiment, the hemp extract is obtained from asupercritical CO₂ extraction. For example, supercritical CO₂ extractionmay be performed as described in U.S. Pat. No. 8,895,078, which isincorporated herein by reference in its entirety. Alternatively, asolvent such as petroleum ether, ethanol, methanol, butanol, acetone,dry ice, or olive oil can be used, at room temperature (ambienttemperature) with stirring, by passive extraction, heated to atemperature above room temperature, or under reflux, as known in the artto provide the hemp extract. In another embodiment, hemp extract from abutanol extraction is employed as starting material for methodsdisclosed herein.

As used herein, the term “flavoring agent” refers to an ingredient thatis added to a composition to impart a particular flavor, smell, or otherorganoleptic property.

As used herein, the term “oil” refers to a nonpolar viscous liquid thatis both hydrophobic and lipophilic. Oils may be isolated from animal,vegetable, or petrochemical products.

As used herein, the term “chew” refers to a product or a portion thereofthat has rheological and other texture and organoleptic properties whichtend to promote chewing upon the article by a target animal. Generallyspeaking, a chewable matrix will exhibit sufficient ductility that it isat least slightly malleable when bitten by the target animal andsufficient palatability that the target animal is not deterred by itstaste from biting it multiple times. By contrast, “chewable” does notmean merely that an article can be chewed by an animal (i.e., it doesnot mean merely that some portion of the article will fit within ananimal's mouth sufficiently to permit engagement of the animal's teethagainst the portion).

The “maximal serum concentration level” of a substance, as used herein,refers to the maximal level of the substance found in a plasma samplefollowing a single administration.

As used herein, the term “cold extrusion” refers to a process forproducing edible food products comprising several unit operationsincluding mixing, kneading, shearing, shaping, and forming, all of whichare conducted at or near ambient temperature.

As used herein, the term “psychotropic effect” refers to a modificationof brain function that results in an alteration of perception, mood,consciousness, or behavior.

Pharmaceutical Compositions

In an aspect, provided herein is a pharmaceutical composition comprisinghemp extract and a carrier, wherein the hemp extract comprises:

cannabidiol;

cannabidiolic acid;

cannabigerolic acid;

Δ9-tetrahydrocannabinol; and

cannabichromene.

In another embodiment, the ratio of Δ9-tetrahydrocannabinol to the othercannabinoids is from about 1:50 to about 1:20. In an embodiment, theratio of cannabidiol to cannabidiolic acid is about 0.1:1 to about1:0.1. In another embodiment, the ratio of cannabidiol to cannabidiolicacid is about 0.1:1, about 0.2:1, about 0.3:1, about 0.4:1, about 0.5:1,about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about1:0.9, about 1:0.8, about 1:0.7, about 1:0.6, about 1:0.5, about 1:0.4,about 1:0.3, about 1:0.2, or about 1:0.1. In yet another embodiment, theratio of cannabidiol to cannabidiolic acid is about 0.6:1 to about1:0.6. In still another embodiment, the ratio of cannabidiol tocannabidiolic acid is about 1:1.

In an embodiment, the concentration of Δ9-tetrahydrocannabinol isinsufficient to produce a psychotropic effect. In another embodiment,the ratio of Δ9-tetrahydrocannabinol to the other cannabinoids is fromabout 1:50 to about 1:20. In yet another embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:50. Instill another embodiment, the ratio of Δ9-tetrahydrocannabinol to theother cannabinoids is about 1:45. In an embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:40. Inanother embodiment, the ratio of Δ9-tetrahydrocannabinol to the othercannabinoids is about 1:35. In yet another embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:30. Instill another embodiment, the ratio of Δ9-tetrahydrocannabinol to theother cannabinoids is about 1:25. In an embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:20.

In an embodiment, the concentration of Δ9-tetrahydrocannabinol is lessthan about 2 mg/mL. In another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 1.5 mg/mL. In yet anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 1 mg/mL. In still another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.9 mg/mL. In yet anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.8 mg/mL. In an embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.7 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.6 mg/mL. In yet another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.5 mg/mL. In still anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.4 mg/mL. In an embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.3 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.2 mg/mL. In yet another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.1 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.

In an embodiment, the hemp extract comprises:

about 0.1-20 mg/mL of cannabidiol;

about 0.1-20 mg/mL of cannabidiolic acid;

about 0.01-0.5 mg/mL cannabigerolic acid;

about 0.01-0.5 mg/mL Δ9-tetrahydrocannabinol; and

about 0.01-0.5 mg/mL cannabichromene.

In another embodiment, the hemp extract comprises:

about 1-10 mg/mL of cannabidiol;

about 1-10 mg/mL of cannabidiolic acid;

about 0.05-0.2 mg/mL cannabigerolic acid;

about 0.1-0.3 mg/mL Δ9-tetrahydrocannabinol; and

about 0.1-0.4 mg/mL cannabichromene.

In yet another embodiment, the hemp extract comprises:

about 5 mg/mL of cannabidiol;

about 5 mg/mL of cannabidiolic acid;

about 0.11 mg/mL cannabigerolic acid;

about 0.25 mg/mL Δ9-tetrahydrocannabinol; and

about 0.27 mg/mL cannabichromene.

In an embodiment, provided herein is a pharmaceutical compositioncomprising hemp extract and a carrier, wherein the hemp extractcomprises:

α-pinene;

β-myrcene;

β-pinene;

δ-limonene;

linalool;

β-caryophyllene;

α-humulene;

nerolidol 2;

guaiol;

caryophyllene oxide; and

α-bisabolol.

In another embodiment, the hemp extract comprises:

about 0.09-0.13% α-pinene;

about 0.23-0.44% β-myrcene;

about 0.04-0.09% β-pinene;

about 0.05-0.09% δ-limonene;

about 0.03-0.06% linalool;

about 0.04-0.07% β-caryophyllene;

about 0.02-0.04% α-humulene;

about 0.04-0.07% nerolidol 2;

about 0.02-0.04% guaiol;

about 0.04-0.08% caryophyllene oxide; and

about 0.01-0.04% α-bisabolol.

In another embodiment, the hemp extract comprises:

about 0.07-0.30% α-pinene;

about 0.10-0.60% β-myrcene;

about 0.02-0.20% β-pinene;

about 0.03-0.20% δ-limonene;

about 0.01-0.08% linalool;

about 0.03-0.09% β-caryophyllene;

about 0.01-0.06% α-humulene;

about 0.02-0.09% nerolidol 2; and

about 0.01-0.06% guaiol;

In another embodiment, the hemp extract comprises:

about 0.01-0.50% α-pinene;

about 0.01-0.90% β-myrcene;

about 0.01-0.50% β-pinene;

about 0.01-0.50% δ-limonene;

about 0.01-0.50% linalool;

about 0.01-0.50% β-caryophyllene;

about 0.01-0.50% α-humulene;

about 0.01-0.50% nerolidol 2;

about 0.01-0.50% guaiol;

about 0.01-0.50% caryophyllene oxide; and

about 0.01-0.50% α-bisabolol.

In another embodiment, the hemp extract further comprises:

camphene;

β-ocimene;

eucalyptol;

isopulegol; and/or

nerolidol 1.

In another embodiment, the hemp extract comprises:

about 0.02% camphene;

about 0.02-0.03% β-ocimene;

about 0.02-0.05% eucalyptol;

about 0.02% isopulegol; and/or

about 0.02-0.04% nerolidol 1.

In another embodiment, the hemp extract comprises:

about 0.01-0.04% camphene;

about 0.01-0.05% β-ocimene;

about 0.01-0.07% eucalyptol;

about 0.01-0.04% isopulegol; and/or

about 0.01-0.05% nerolidol 1.

In another embodiment, the hemp extract comprises:

about 0.01-0.50% camphene;

about 0.01-0.50% β-ocimene;

about 0.01-0.50% eucalyptol;

about 0.01-0.50% isopulegol; and/or

about 0.01-0.50% nerolidol 1.

In an embodiment, the hemp extract comprises 1 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 2 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 3 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 4 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 5 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 6 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 7 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 8 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 9 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 10 or more of thefollowing: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool,β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide,α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol1.

In an embodiment, the hemp extract comprises 11 or more of thefollowing: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool,β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide,α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol1.

In an embodiment, the hemp extract comprises 12 or more of thefollowing: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool,β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide,α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol1.

In an embodiment, the hemp extract comprises 13 or more of thefollowing: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool,β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide,α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol1.

In an embodiment, the hemp extract comprises 14 or more of thefollowing: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool,β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide,α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol1.

In an embodiment, the hemp extract comprises 15 or more of thefollowing: α-pinene, β-myrcene, β-pinene, δ-limonene, linalool,β-caryophyllene, α-humulene, nerolidol 2, guaiol, caryophyllene oxide,α-bisabolol, camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol1.

In an embodiment, the hemp extract comprises the following: α-pinene,β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene,nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene,β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the composition is formulated as an oil. In anotherembodiment, the carrier is selected from the group consisting of linseedoil, olive oil, fish oil, salmon oil, coconut oil, catnip oil andgrapeseed oil. In yet another embodiment, the carrier is grapeseed oil.

In an embodiment, the dosage form comprises nepetalactone.

In an embodiment, the dosage form comprises taurine.

In an embodiment, the pharmaceutical composition is formulated as asublingual spray. In still another embodiment, the pharmaceuticalcomposition is formulated as a water or alcohol soluble solution, a gel,or a cream for transdermal application. In an embodiment, the dosageform is formulated as a gel for buccal or mucosal administration. In anembodiment, the pharmaceutical composition is formulated as a powder. Inanother embodiment, the pharmaceutical composition is formulated as asolution for subcutaneous injection. In yet another embodiment, thepharmaceutical composition is formulated as a tablet. In still anotherembodiment, the pharmaceutical composition is formulated as a capsule.In an embodiment, the pharmaceutical composition is formulated as a hardchewable.

In an embodiment, the composition is formulated as a chew for oraladministration. In another embodiment, the chew is produced using coldextrusion. In another embodiment, the weight of the chew is about 0.5-10g. In yet another embodiment, the weight of the chew is about 4 g, about6 g, about 9 g, or about 10 g. In still another embodiment, the weightof the chew is about 0.5 g. In an embodiment, the weight of the chew isabout 1 g. In another embodiment, the weight of the chew is about 1.5 g.In yet another embodiment, the weight of the chew is about 2 g. In stillanother embodiment, the weight of the chew is about 3 g. In anembodiment, the weight of the chew is about 4 g. In another embodiment,the weight of the chew is about 5 g. In yet another embodiment, theweight of the chew is about 6 g. In still another embodiment, the weightof the chew is about 7 g. In an embodiment, the weight of the chew isabout 8 g. In another embodiment, the weight of the chew is about 9 g.In yet another embodiment, the weight of the chew is about 10 g.

In an embodiment, the 4 g chew comprises:

about 7 mg of cannabidiol;

about 6 mg of cannabidiolic acid;

about 0.12 mg cannabigerolic acid;

about 0.32 mg Δ9-tetrahydrocannabinol; and

about 0.36 mg cannabichromene.

The pharmaceutical compositions of the present disclosure may bemanufactured by processes well known in the art, e.g., by means ofconventional mixing, dissolving, granulating, grinding, pulverizing,dragee-making, levigating, emulsifying, encapsulating, entrapping or bylyophilizing processes.

The compositions for use in accordance with the present disclosure thusmay be formulated in conventional manner using one or morepharmaceutically acceptable carriers comprising excipients andauxiliaries, which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

Dosage Forms

In an aspect, provided herein is a dosage form comprising:

cannabidiol;

cannabidiolic acid;

cannabigerolic acid;

Δ9-tetrahydrocannabinol;

cannabichromene; and

one or more pharmaceutically acceptable additives, flavoring agents,surfactants, and adjuvants.

In an embodiment, the ratio of cannabidiol to cannabidiolic acid isselected from the group consisting of about 1:100, about 1:50, about1:10, and about 1:1. In an embodiment, the ratio of cannabidiol tocannabidiolic acid is about 0.1:1 to about 1:0.1. In another embodiment,the ratio of cannabidiol to cannabidiolic acid is about 0.1:1, about0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1,about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2,or about 1:0.1. In yet another embodiment, the ratio of cannabidiol tocannabidiolic acid is about 0.6:1 to about 1:0.6. In still anotherembodiment, the ratio of cannabidiol to cannabidiolic acid is about 1:1.

In an embodiment, the concentration of Δ9-tetrahydrocannabinol isinsufficient to produce a psychotropic effect. In another embodiment,the ratio of Δ9-tetrahydrocannabinol to the other cannabinoids is fromabout 1:50 to about 1:20. In yet another embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:50. Instill another embodiment, the ratio of Δ9-tetrahydrocannabinol to theother cannabinoids is about 1:45. In an embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:40. Inanother embodiment, the ratio of Δ9-tetrahydrocannabinol to the othercannabinoids is about 1:35. In yet another embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:30. Instill another embodiment, the ratio of Δ9-tetrahydrocannabinol to theother cannabinoids is about 1:25. In an embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:20.

In an embodiment, the concentration of Δ9-tetrahydrocannabinol is lessthan about 2 mg/mL. In another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 1.5 mg/mL. In yet anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 1 mg/mL. In still another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.9 mg/mL. In yet anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.8 mg/mL. In an embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.7 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.6 mg/mL. In yet another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.5 mg/mL. In still anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.4 mg/mL. In an embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.3 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.2 mg/mL. In yet another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.1 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.

In an embodiment, the dosage form comprises:

about 0.1-20 mg/mL of cannabidiol;

about 0.1-20 mg/mL of cannabidiolic acid;

about 0.01-0.5 mg/mL cannabigerolic acid;

about 0.01-0.5 mg/mL Δ9-tetrahydrocannabinol; and

about 0.01-0.5 mg/mL cannabichromene.

In another embodiment, the dosage form comprises:

about 1-10 mg/mL of cannabidiol;

about 1-10 mg/mL of cannabidiolic acid;

about 0.05-0.2 mg/mL cannabigerolic acid;

about 0.1-0.3 mg/mL Δ9-tetrahydrocannabinol; and

about 0.1-0.4 mg/mL cannabichromene.

In yet another embodiment, the dosage form comprises:

about 5 mg/mL of cannabidiol;

about 5 mg/mL of cannabidiolic acid;

about 0.11 mg/mL cannabigerolic acid;

about 0.25 mg/mL Δ9-tetrahydrocannabinol; and

about 0.27 mg/mL cannabichromene.

In some embodiments, the dosage form comprises:

α-pinene;

β-myrcene;

β-pinene;

δ-limonene;

linalool;

β-caryophyllene;

α-humulene;

nerolidol 2;

guaiol;

caryophyllene oxide; and

α-bisabolol.

In another embodiment, the dosage form comprises:

about 0.09-0.13% α-pinene;

about 0.23-0.44% β-myrcene;

about 0.04-0.09% β-pinene;

about 0.05-0.09% δ-limonene;

about 0.03-0.06% linalool;

about 0.04-0.07% β-caryophyllene;

about 0.02-0.04% α-humulene;

about 0.04-0.07% nerolidol 2;

about 0.02-0.04% guaiol;

about 0.04-0.08% caryophyllene oxide; and

about 0.01-0.04% α-bisabolol.

In another embodiment, the dosage form comprises:

about 0.07-0.30% α-pinene;

about 0.10-0.60% β-myrcene;

about 0.02-0.20% β-pinene;

about 0.03-0.20% δ-limonene;

about 0.01-0.08% linalool;

about 0.03-0.09% β-caryophyllene;

about 0.01-0.06% α-humulene;

about 0.02-0.09% nerolidol 2; and

about 0.01-0.06% guaiol;

In another embodiment, the dosage form comprises:

about 0.01-0.50% α-pinene;

about 0.01-0.90% β-myrcene;

about 0.01-0.50% β-pinene;

about 0.01-0.50% δ-limonene;

about 0.01-0.50% linalool;

about 0.01-0.50% β-caryophyllene;

about 0.01-0.50% α-humulene;

about 0.01-0.50% nerolidol 2;

about 0.01-0.50% guaiol;

about 0.01-0.50% caryophyllene oxide; and

about 0.01-0.50% α-bisabolol.

In another embodiment, the dosage form further comprises:

camphene;

β-ocimene;

eucalyptol;

isopulegol; and/or

nerolidol 1.

In another embodiment, the dosage form comprises:

about 0.02% camphene;

about 0.02-0.03% β-ocimene;

about 0.02-0.05% eucalyptol;

about 0.02% isopulegol; and/or

about 0.02-0.04% nerolidol 1.

In another embodiment, the dosage form comprises:

about 0.01-0.04% camphene;

about 0.01-0.05% β-ocimene;

about 0.01-0.07% eucalyptol;

about 0.01-0.04% isopulegol; and/or

about 0.01-0.05% nerolidol 1.

In another embodiment, the dosage form comprises:

about 0.01-0.50% camphene;

about 0.01-0.50% β-ocimene;

about 0.01-0.50% eucalyptol;

about 0.01-0.50% isopulegol; and/or

about 0.01-0.50% nerolidol 1.

In an embodiment, the hemp extract comprises 1 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 2 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 3 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the hemp extract comprises 4 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 5 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 6 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 7 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 8 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 9 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 10 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 11 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 12 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 13 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 14 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises 15 or more of the following:α-pinene, β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene,α-humulene, nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol,camphene, β-ocimene, eucalyptol, isopulegol, and nerolidol 1.

In an embodiment, the dosage form comprises the following: α-pinene,β-myrcene, β-pinene, δ-limonene, linalool, β-caryophyllene, α-humulene,nerolidol 2, guaiol, caryophyllene oxide, α-bisabolol, camphene,β-ocimene, eucalyptol, isopulegol, and nerolidol 1

In an embodiment, the flavoring agent is selected from the groupconsisting of catnip oil, peppermint oil, mango extract, beef, poultry,and seafood.

In an embodiment, the dosage form is formulated as a sublingual spray.In still another embodiment, the dosage form is formulated as a water oralcohol soluble solution, a gel, or a cream for transdermal application.In an embodiment, the dosage form is formulated as a powder. In anembodiment, the dosage form is formulated as a gel for buccal or mucosaladministration. In another embodiment, the dosage form is formulated asa solution for subcutaneous injection. In yet another embodiment, thedosage form is formulated as a tablet. In still another embodiment, thedosage form is formulated as a capsule. In an embodiment, the dosageform is formulated as a hard chewable.

In some embodiments, the invention includes infusing edible productswith hemp extract. In another embodiment, the edible product is anextruded food product, baked food product, nut butter, spread, pelletedfeed, or processed food. In another embodiment, the edible product is apet food. In another embodiment the pet food is in a dry, shelf-stableform such as dried meals, dried fish, dried dairy products, fish meal,fish flour, cereals, flours, carbohydrates, dried fruits, etc. Inanother embodiment, the pet food is moist or semi-moist. In anotherembodiment, the pet food contains food additives or supplements such asvitamins, minerals, medicinals, etc., for example chemicals, enzymes,etc., capable of removing plaque or tartar from the animal's teeth, etc.

In an embodiment, the hemp extract is administered with catnip oil. Inanother embodiment, any of the dosage forms described can also includecatnip.

In another embodiment, hemp extracts are administered using a nebulizer.In another embodiment, the nebulizer delivery device and system iscapable of effectively and efficiently administering one or morenebulized drug to an animal. In another embodiment, the nebulizer systemcan easily be used on animals without removing them from their naturalenvironment. In another embodiment, the nebulizer delivery device andsystem enables animals to be easily treated daily or multiple times aday without undue stress or the need for extensive resources. In anotherembodiment, the nebulizer delivery device and system can be used onanimals having varying levels of training.

In one embodiment, hemp extract is administered using a diffuser. Thediffuser can be any device which disperses hemp extract into the air.Hemp extract may be dispersed by any method, including by naturalconvection, by forced convection, by heating a wick or pad, for example,holding the hemp extract, by using pumps, or with fans.

In one embodiment, hemp extract is administered by a pet collar. The petcollar may comprise a belt with a buckle on one side, a free end on theother side and an attachment means, such as apertures disposedlongitudinally within the central portion of the belt, or a quickrelease clasp mechanism, for securing the collar in a closed loopconfiguration. The pet collar may be made from a variety of materialsincluding nylon, polyester leather or other suitable material. The beltmaterial may be treated with a water-proofing compound. The nylon orpolyester belt may be interwoven with reflective fibers to enhance thevisibility of the pet collar during nighttime hours. In one embodiment,the collar is infused with hemp extract.

Chews

In an embodiment, the dosage form is formulated as a chew for oraladministration. In another embodiment, the chew is produced using coldextrusion. In another embodiment, the weight of the chew is about 0.5-10g. In yet another embodiment, the weight of the chew is about 4 g, about6 g, about 9 g, or about 10 g. In still another embodiment, the weightof the chew is about 0.5 g. In an embodiment, the weight of the chew isabout 1 g. In another embodiment, the weight of the chew is about 1.5 g.In yet another embodiment, the weight of the chew is about 2 g. In stillanother embodiment, the weight of the chew is about 3 g. In anembodiment, the weight of the chew is about 4 g. In another embodiment,the weight of the chew is about 5 g. In yet another embodiment, theweight of the chew is about 6 g. In still another embodiment, the weightof the chew is about 7 g. In an embodiment, the weight of the chew isabout 8 g. In another embodiment, the weight of the chew is about 9 g.In yet another embodiment, the weight of the chew is about 10 g.

In one embodiment, the dosage form comprises:

glucosamine HCl;

chondroitin sulfate (76%);

brewer's yeast;

arabic gum;

guar gum;

a flavoring agent;

Verdilox;

Previon;

hemp extract;

glycerin;

sunflower lecithin; and

water.

In another embodiment, the dosage form comprises:

about 10-20% glucosamine HCl;

about 0.1-7% chondroitin sulfate (76%);

about 25-35% brewer's yeast;

about 1-10% arabic gum;

about 0.1-4% guar gum;

about 10-20% of a flavoring agent;

about 0.01-1% Verdilox;

about 0.1-2% Previon;

about 1-10% hemp extract;

about 10-20% glycerin;

about 1-10% sunflower lecithin; and

about 1-10% water.

In another embodiment, the dosage form comprises:

about 12-17% glucosamine HCl;

about 1-4% chondroitin sulfate (76%);

about 29-33% brewer's yeast;

about 3-6% arabic gum;

about 0.5-2% guar gum;

about 12-16% of a flavoring agent;

about 0.01-0.1% Verdilox;

about 0.5-1.5% Previon;

about 3-6% hemp extract;

about 13-17% glycerin;

about 3-7% sunflower lecithin; and

about 3-7% water.

In yet another embodiment, the dosage form comprises:

about 15.6% glucosamine HCl;

about 2.6% chondroitin sulfate (76%);

about 30% brewer's yeast;

about 4.7% arabic gum;

about 0.9% guar gum;

about 14.2% of a flavoring agent;

about 0.05% Verdilox;

about 0.9% Previon;

about 4.7% hemp extract;

about 15.1% glycerin;

about 5.7% sunflower lecithin; and

about 5.7% water.

In another embodiment, the dosage form comprises:

glucosamine HCl;

hyaluronic acid;

brewer's yeast;

arabic gum;

guar gum;

a flavoring agent;

Verdilox;

Previon;

hemp extract;

glycerin;

sunflower lecithin; and

water.

In another embodiment, the dosage form comprises:

about 10-20% glucosamine HCl;

about 0.01-3% hyaluronic acid;

about 25-35% brewer's yeast;

about 1-10% arabic gum;

about 0.1-5% guar gum;

about 10-20% of a flavoring agent;

about 0.01-1% Verdilox;

about 0.1-3% Previon;

about 1-10% hemp extract;

about 10-20% glycerin;

about 1-10% sunflower lecithin; and

about 1-10% water.

In another embodiment, the dosage form comprises:

about 12-17% glucosamine HCl;

about 0.01-1% hyaluronic acid;

about 29-33% brewer's yeast;

about 3-6% arabic gum;

about 0.5-2% guar gum;

about 12-16% of a flavoring agent;

about 0.01-0.1% Verdilox;

about 0.5-1.5% Previon;

about 3-6% hemp extract;

about 13-17% glycerin;

about 3-7% sunflower lecithin; and

about 3-7% water.

In yet another embodiment, the dosage form comprises:

about 16% glucosamine HCl;

about 0.1% hyaluronic acid;

about 30.6% brewer's yeast;

about 4.8% arabic gum;

about 0.97% guar gum;

about 14.5% of a flavoring agent;

about 0.05% Verdilox;

about 0.97% Previon;

about 4.8% hemp extract;

about 15.5% glycerin;

about 5.8% sunflower lecithin; and

about 5.8% water.

In yet another embodiment, the dosage form comprises:

hemp extract;

peanut butter;

rice bran;

glucosamine HCL;

sweet potato;

dry molasses;

sorbic acid

brewer's yeast;

sugar;

water;

glycerin;

potato starch;

dehydrated peanut butter;

rice starch; and

guar gum.

In yet another embodiment, the dosage form comprises:

about 5.0% hemp extract;

about 15.0% peanut butter;

about 12.5% rice bran;

about 12.75% glucosamine HCL;

about 5.5% sweet potato;

about 8.0% dry molasses;

about 1% sorbic acid;

about 5.0% brewer's yeast;

about 6.0% sugar;

about 9.25% water;

about 13.0 glycerin;

about 2.0% potato starch;

about 1.0% dehydrated peanut butter;

about 2.0% rice starch; and

about 2.0% guar gum.

In yet another embodiment, the dosage form comprises:

about 5.0% hemp extract;

about 15.0% peanut butter;

about 13.0% rice bran;

about 8.5% glucosamine HCL;

about 6.0% sweet potato;

about 9.0% dry molasses;

about 1% sorbic acid;

about 5.0% brewer's yeast;

about 6.0% sugar;

about 9.5% water;

about 13.0 glycerin;

about 4.0% potato starch;

about 1.0% dehydrated peanut butter;

about 2.0% rice starch; and

about 2.0% guar gum.

In yet another embodiment, the dosage form comprises:

about 3.0-10.0% hemp extract;

about 10.0-20.0% peanut butter;

about 10.0-15.0% rice bran;

about 5.0-15.0% glucosamine HCL;

about 4.0-10.0% sweet potato;

about 6.0-13.0% dry molasses;

about 0.5-5.0% sorbic acid;

about 2.0-8.0% brewer's yeast;

about 3.0-8.0% sugar;

about 5.0-15.0% water;

about 8.0-18.0% glycerin;

about 1.0-8.0% potato starch;

about 0.5-5.0% dehydrated peanut butter;

about 1.0-5.0% rice starch; and

about 1.0-5.0% guar gum.

In another embodiment, the dosage form comprises 2.0% hemp extract. Inanother embodiment, the dosage form comprises 3.0% hemp extract. Inanother embodiment, the dosage form comprises 4.0% hemp extract. Inanother embodiment, the dosage form comprises 5.0% hemp extract. Inanother embodiment, the dosage form comprises 6.0% hemp extract. Inanother embodiment, the dosage form comprises 7.0% hemp extract. Inanother embodiment, the dosage form comprises 8.0% hemp extract. Inanother embodiment, the dosage form comprises 9.0% hemp extract. Inanother embodiment, the dosage form comprises 10.0% hemp extract.

In an embodiment, the hemp extract comprises:

cannabidiol;

cannabidiolic acid;

cannabigerolic acid;

Δ9-tetrahydrocannabinol; and

cannabichromene.

In an embodiment, the ratio of cannabidiol to cannabidiolic acid isselected from the group consisting of about 1:100, about 1:50, about1:10, and about 1:1. In an embodiment, the ratio of cannabidiol tocannabidiolic acid is about 0.1:1 to about 1:0.1. In another embodiment,the ratio of cannabidiol to cannabidiolic acid is about 0.1:1, about0.2:1, about 0.3:1, about 0.4:1, about 0.5:1, about 0.6:1, about 0.7:1,about 0.8:1, about 0.9:1, about 1:1, about 1:0.9, about 1:0.8, about1:0.7, about 1:0.6, about 1:0.5, about 1:0.4, about 1:0.3, about 1:0.2,or about 1:0.1. In yet another embodiment, the ratio of cannabidiol tocannabidiolic acid is about 0.6:1 to about 1:0.6. In still anotherembodiment, the ratio of cannabidiol to cannabidiolic acid is about 1:1.

In an embodiment, the concentration of Δ9-tetrahydrocannabinol isinsufficient to produce a psychotropic effect. In another embodiment,the ratio of Δ9-tetrahydrocannabinol to the other cannabinoids is fromabout 1:50 to about 1:20. In yet another embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:50. Instill another embodiment, the ratio of Δ9-tetrahydrocannabinol to theother cannabinoids is about 1:45. In an embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:40. Inanother embodiment, the ratio of Δ9-tetrahydrocannabinol to the othercannabinoids is about 1:35. In yet another embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:30. Instill another embodiment, the ratio of Δ9-tetrahydrocannabinol to theother cannabinoids is about 1:25. In an embodiment, the ratio ofΔ9-tetrahydrocannabinol to the other cannabinoids is about 1:20.

In an embodiment, the concentration of Δ9-tetrahydrocannabinol is lessthan about 2 mg/mL. In another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 1.5 mg/mL. In yet anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 1 mg/mL. In still another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.9 mg/mL. In yet anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.8 mg/mL. In an embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.7 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.6 mg/mL. In yet another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.5 mg/mL. In still anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.4 mg/mL. In an embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.3 mg/mL. In anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is less thanabout 0.2 mg/mL. In yet another embodiment, the concentration ofΔ9-tetrahydrocannabinol is less than about 0.1 mg/mL. In yet anotherembodiment, the concentration of Δ9-tetrahydrocannabinol is about 0mg/mL.

In an embodiment, the hemp extract comprises:

about 0.1-20 mg/mL of cannabidiol;

about 0.1-20 mg/mL of cannabidiolic acid;

about 0.01-0.5 mg/mL cannabigerolic acid;

about 0.01-0.5 mg/mL Δ9-tetrahydrocannabinol; and

about 0.01-0.5 mg/mL cannabichromene.

In another embodiment, the hemp extract comprises:

about 1-10 mg/mL of cannabidiol;

about 1-10 mg/mL of cannabidiolic acid;

about 0.05-0.2 mg/mL cannabigerolic acid;

about 0.1-0.3 mg/mL Δ9-tetrahydrocannabinol; and

about 0.1-0.4 mg/mL cannabichromene.

In yet another embodiment, the hemp extract comprises:

about 5 mg/mL of cannabidiol;

about 5 mg/mL of cannabidiolic acid;

about 0.11 mg/mL cannabigerolic acid;

about 0.25 mg/mL Δ9-tetrahydrocannabinol; and

about 0.27 mg/mL cannabichromene.

In an embodiment, the hemp extract comprises:

α-pinene;

β-myrcene;

β-pinene;

δ-limonene;

linalool;

β-caryophyllene;

α-humulene;

nerolidol 2;

guaiol;

caryophyllene oxide; and

α-bisabolol.

In another embodiment, the hemp extract comprises:

about 0.09-0.13% α-pinene;

about 0.23-0.44% β-myrcene;

about 0.04-0.09% β-pinene;

about 0.05-0.09% δ-limonene;

about 0.03-0.06% linalool;

about 0.04-0.07% β-caryophyllene;

about 0.02-0.04% α-humulene;

about 0.04-0.07% nerolidol 2;

about 0.02-0.04% guaiol;

about 0.04-0.08% caryophyllene oxide; and

about 0.01-0.04% α-bisabolol.

In another embodiment, the hemp extract comprises:

about 0.07-0.30% α-pinene;

about 0.10-0.60% β-myrcene;

about 0.02-0.20% β-pinene;

about 0.03-0.20% δ-limonene;

about 0.01-0.08% linalool;

about 0.03-0.09% β-caryophyllene;

about 0.01-0.06% α-humulene;

about 0.02-0.09% nerolidol 2; and

about 0.01-0.06% guaiol;

In another embodiment, the hemp extract comprises:

about 0.01-0.50% α-pinene;

about 0.01-0.90% β-myrcene;

about 0.01-0.50% β-pinene;

about 0.01-0.50% δ-limonene;

about 0.01-0.50% linalool;

about 0.01-0.50% β-caryophyllene;

about 0.01-0.50% α-humulene;

about 0.01-0.50% nerolidol 2;

about 0.01-0.50% guaiol;

about 0.01-0.50% caryophyllene oxide; and

about 0.01-0.50% α-bisabolol.

In another embodiment, the hemp extract further comprises:

camphene;

β-ocimene;

eucalyptol;

isopulegol; and/or

nerolidol 1.

In another embodiment, the hemp extract comprises:

about 0.02% camphene;

about 0.02-0.03% β-ocimene;

about 0.02-0.05% eucalyptol;

about 0.02% isopulegol; and/or

about 0.02-0.04% nerolidol 1.

In another embodiment, the hemp extract comprises:

about 0.01-0.04% camphene;

about 0.01-0.05% β-ocimene;

about 0.01-0.07% eucalyptol;

about 0.01-0.04% isopulegol; and/or

about 0.01-0.05% nerolidol 1.

In another embodiment, the hemp extract comprises:

about 0.01-0.50% camphene;

about 0.01-0.50% β-ocimene;

about 0.01-0.50% eucalyptol;

about 0.01-0.50% isopulegol; and/or

about 0.01-0.50% nerolidol 1.

In an embodiment, the composition is formulated as an oil. In anotherembodiment, the carrier is selected from the group consisting of linseedoil, olive oil, fish oil, salmon oil, coconut oil, catnip oil andgrapeseed oil. In yet another embodiment, the carrier is grapeseed oil.

In an embodiment, the flavoring agent is selected from the groupconsisting of catnip oil, chicken liver powder, poultry extract,maltodextrin, butter, and bacon. In another embodiment, the flavoringagent is chicken liver powder.

In an embodiment, the composition is formulated as a chew for oraladministration. In another embodiment, the chew is produced using coldextrusion. In another embodiment, the weight of the chew is about 0.5-10g. In yet another embodiment, the weight of the chew is about 4 g, about6 g, about 9 g, or about 10 g. In still another embodiment, the weightof the chew is about 0.5 g. In an embodiment, the weight of the chew isabout 1 g. In another embodiment, the weight of the chew is about 1.5 g.In yet another embodiment, the weight of the chew is about 2 g. In stillanother embodiment, the weight of the chew is about 3 g. In anembodiment, the weight of the chew is about 4 g. In another embodiment,the weight of the chew is about 5 g. In yet another embodiment, theweight of the chew is about 6 g. In still another embodiment, the weightof the chew is about 7 g. In an embodiment, the weight of the chew isabout 8 g. In another embodiment, the weight of the chew is about 9 g.In yet another embodiment, the weight of the chew is about 10 g.

In an embodiment, the 4 g chew comprises:

about 7 mg of cannabidiol;

about 6 mg of cannabidiolic acid;

about 0.12 mg cannabigerolic acid;

about 0.32 mg Δ9-tetrahydrocannabinol; and

about 0.36 mg cannabichromene.

Methods of Treatment

In an aspect, provided herein is a method for treating or reducing painin a veterinary subject in need thereof, comprising administering to thesubject a therapeutically effective amount of any of the compositions ordosage forms described above.

In an embodiment, the pain is associated with arthritis, post-operativepain, acute pain, dental pain, pain associated with gingivitis, ormulti-joint pain.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 0.1-15.0 mg/kg. In another embodiment,the pharmaceutical composition or dosage form is administered at adosage of about 0.1-10.0 mg/kg. In yet another embodiment, thepharmaceutical composition or dosage form is administered at a dosage ofabout 0.1 mg/kg. In still another embodiment, the pharmaceuticalcomposition or dosage form is administered at a dosage of about 0.2mg/kg. In yet another embodiment, the pharmaceutical composition ordosage form is administered at a dosage of about 0.3 mg/kg. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 0.4 mg/kg. In another embodiment, thepharmaceutical composition or dosage form is administered at a dosage ofabout 0.5 mg/kg. In yet another embodiment, the pharmaceuticalcomposition or dosage form is administered at a dosage of about 0.6mg/kg. In still another embodiment, the pharmaceutical composition ordosage form is administered at a dosage of about 0.7 mg/kg. In yetanother embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 0.8 mg/kg. In an embodiment, thepharmaceutical composition or dosage form is administered at a dosage ofabout 0.9 mg/kg. In another embodiment, the pharmaceutical compositionor dosage form is administered at a dosage of about 1 mg/kg. In yetanother embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1.5 mg/kg. In still anotherembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2 mg/kg. In an embodiment, thepharmaceutical composition or dosage form is administered at a dosage ofabout 3 mg/kg. In another embodiment, the pharmaceutical composition ordosage form is administered at a dosage of about 4 mg/kg. In yet anotherembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 5 mg/kg. In still another embodiment,the pharmaceutical composition or dosage form is administered at adosage of about 6 mg/kg. In an embodiment, the pharmaceuticalcomposition or dosage form is administered at a dosage of about 7 mg/kg.In another embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 8 mg/kg. In yet another embodiment,the pharmaceutical composition or dosage form is administered at adosage of about 9 mg/kg. In still another embodiment, the pharmaceuticalcomposition or dosage form is administered at a dosage of about 10mg/kg. In an embodiment, the pharmaceutical composition or dosage formis administered at a dosage of about 11 mg/kg. In another embodiment,the pharmaceutical composition or dosage form is administered at adosage of about 12 mg/kg. In yet another embodiment, the pharmaceuticalcomposition or dosage form is administered at a dosage of about 13mg/kg. In still another embodiment, the pharmaceutical composition ordosage form is administered at a dosage of about 14 mg/kg. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 15 mg/kg.

In another embodiment, the pharmaceutical composition or dosage form isadministered at twice the therapeutically effective dosage for one week,and then subsequently administered at a therapeutically effectivedosage. In yet another embodiment, the therapeutically effective dosageis about 0.1-0.5 mg/kg. In still another embodiment, the therapeuticallyeffective dosage is about 2 mg/kg. In an embodiment, the therapeuticallyeffective dosage is about 8 mg/kg.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1 mg/kg for one week, and thensubsequently administered at a dosage of about 0.1-0.5 mg/kg. In anotherembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 4 mg/kg for one week, and thensubsequently administered at a dosage of about 2 mg/kg.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2 mg/kg every 12 hours for two weeks,then subsequently administered at a dosage of about 1 mg/kg every 12hours for two weeks, and then subsequently administered at a dosage ofabout 2 mg/kg every 12 hours for four weeks.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 1.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 2.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 3.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 3.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 3.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 3.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 4.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 4.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 4.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 4.0 mg/kg four times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 5.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 5.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 5.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 5.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 6.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 6.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 6.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 6.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 7.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 7.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 7.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 7.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 8.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 8.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 8.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 8.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 9.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 9.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 9.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 9.0 mg/kg four times daily.

In an embodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 10.0 mg/kg once daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 10.0 mg/kg twice daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 10.0 mg/kg three times daily. In anembodiment, the pharmaceutical composition or dosage form isadministered at a dosage of about 10.0 mg/kg four times daily.

In an embodiment, the method results in a therapeutically effectivemedian maximal serum concentration of cannabidiol. In anotherembodiment, the median maximal serum concentration of cannabidiol isabout 90-310 ng/mL. In yet another embodiment, the median maximal serumconcentration of cannabidiol is about 90 ng/mL. In still anotherembodiment, the median maximal serum concentration of cannabidiol isabout 100 ng/mL. In still another embodiment, the median maximal serumconcentration of cannabidiol is about 102 ng/mL. In an embodiment, themedian maximal serum concentration of cannabidiol is about 200 ng/mL. Inanother embodiment, the median maximal serum concentration ofcannabidiol is about 300 ng/mL. In yet another embodiment, the medianmaximal serum concentration of cannabidiol is about 400 ng/mL. In stillanother embodiment, the median maximal serum concentration ofcannabidiol is about 500 ng/mL. In an embodiment, the median maximalserum concentration of cannabidiol is about 590 ng/mL. In anotherembodiment, the median maximal serum concentration of cannabidiol isabout 600 ng/mL.

In an embodiment, the veterinary subject is canine, feline, bovine,porcine, or equine. In another embodiment, the veterinary subject iscanine. In yet another embodiment, the veterinary subject is feline.

In an aspect, provided herein is a method for treating or reducing painassociated with arthritis, post-operative pain, acute pain, dental pain,pain associated with gingivitis, or multi-joint pain in a veterinarysubject in need thereof, comprising administering to the subject atherapeutically effective amount of hemp extract.

In an embodiment, the hemp extract is administered at a dosage of about0.1-15.0 mg/kg. In another embodiment, the hemp extract is administeredat a dosage of about 0.1-10.0 mg/kg. In yet another embodiment, the hempextract is administered at a dosage of about 0.1 mg/kg. In still anotherembodiment, the hemp extract is administered at a dosage of about 0.2mg/kg. In yet another embodiment, the hemp extract is administered at adosage of about 0.3 mg/kg. In an embodiment, the hemp extract isadministered at a dosage of about 0.4 mg/kg. In another embodiment, thehemp extract is administered at a dosage of about 0.5 mg/kg. In yetanother embodiment, the hemp extract is administered at a dosage ofabout 0.6 mg/kg. In still another embodiment, the hemp extract isadministered at a dosage of about 0.7 mg/kg. In yet another embodiment,the hemp extract is administered at a dosage of about 0.8 mg/kg. In anembodiment, the hemp extract is administered at a dosage of about 0.9mg/kg. In another embodiment, the hemp extract is administered at adosage of about 1 mg/kg. In yet another embodiment, the hemp extract isadministered at a dosage of about 1.5 mg/kg. In still anotherembodiment, the hemp extract is administered at a dosage of about 2mg/kg. In an embodiment, the hemp extract is administered at a dosage ofabout 3 mg/kg. In another embodiment, the hemp extract is administeredat a dosage of about 4 mg/kg. In yet another embodiment, the hempextract is administered at a dosage of about 5 mg/kg. In still anotherembodiment, the hemp extract is administered at a dosage of about 6mg/kg. In an embodiment, the hemp extract is administered at a dosage ofabout 7 mg/kg. In another embodiment, the hemp extract is administeredat a dosage of about 8 mg/kg. In yet another embodiment, the hempextract is administered at a dosage of about 9 mg/kg. In still anotherembodiment, the hemp extract is administered at a dosage of about 10mg/kg. In an embodiment, the hemp extract is administered at a dosage ofabout 11 mg/kg. In another embodiment, the hemp extract is administeredat a dosage of about 12 mg/kg. In yet another embodiment, the hempextract is administered at a dosage of about 13 mg/kg. In still anotherembodiment, the hemp extract is administered at a dosage of about 14mg/kg. In an embodiment, the hemp extract is administered at a dosage ofabout 15 mg/kg.

In another embodiment, the hemp extract is administered at twice thetherapeutically effective dosage for one week, and then subsequentlyadministered at a therapeutically effective dosage. In yet anotherembodiment, the therapeutically effective dosage is about 0.1-0.5 mg/kg.In still another embodiment, the therapeutically effective dosage isabout 2 mg/kg. In an embodiment, the therapeutically effective dosage isabout 8 mg/kg.

In an embodiment, the hemp extract is administered at a dosage of about1 mg/kg for one week, and then subsequently administered at a dosage ofabout 0.1-0.5 mg/kg. In another embodiment, the hemp extract isadministered at a dosage of about 4 mg/kg for one week, and thensubsequently administered at a dosage of about 2 mg/kg.

In an embodiment, the method results in a therapeutically effectivemedian maximal serum concentration of cannabidiol. In anotherembodiment, the median maximal serum concentration of cannabidiol isabout 90-310 ng/mL. In yet another embodiment, the median maximal serumconcentration of cannabidiol is about 90 ng/mL. In still anotherembodiment, the median maximal serum concentration of cannabidiol isabout 100 ng/mL. In still another embodiment, the median maximal serumconcentration of cannabidiol is about 102 ng/mL. In an embodiment, themedian maximal serum concentration of cannabidiol is about 200 ng/mL. Inanother embodiment, the median maximal serum concentration ofcannabidiol is about 300 ng/mL. In yet another embodiment, the medianmaximal serum concentration of cannabidiol is about 400 ng/mL. In stillanother embodiment, the median maximal serum concentration ofcannabidiol is about 500 ng/mL. In an embodiment, the median maximalserum concentration of cannabidiol is about 590 ng/mL. In anotherembodiment, the median maximal serum concentration of cannabidiol isabout 600 ng/mL.

In an embodiment, the veterinary subject is canine, feline, bovine,porcine, or equine. In another embodiment, the veterinary subject iscanine. In yet another embodiment, the veterinary subject is feline.

The pharmaceutical compositions and dosage forms of the presentdisclosure may be administered by any convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa,etc.) and may be administered together with any other therapeutic agent.Administration can be systemic or local.

The therapeutic compositions of the invention will be administered withsuitable carriers, excipients, and other agents that are incorporatedinto formulations to provide improved transfer, delivery, tolerance, andthe like. A multitude of appropriate formulations can be found in theformulary known to all pharmaceutical chemists: Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, PA. Theseformulations include, for example, powders, pastes, ointments, jellies,waxes, oils, lipids, lipid (cationic or anionic) containing vesicles(such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes,oil-in-water and water-in-oil emulsions, emulsions carbowax(polyethylene glycols of various molecular weights), semi-solid gels,and semi-solid mixtures containing carbowax. See also Powell et al.“Compendium of excipients for parenteral formulations” PDA (1998) JPharm Sci Technol 52:238-311.

The dose may vary depending upon the age and the weight of a subject tobe administered, target disease, conditions, route of administration,and the like. Various delivery systems are known and can be used toadminister the pharmaceutical composition of the invention, e.g.,encapsulation in liposomes, microparticles, microcapsules, receptormediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem.262:4429-4432). Methods of introduction include, but are not limited to,intradermal, intramuscular, intraperitoneal, intravenous, transdermal,buccal, sublingual, subcutaneous, intranasal, epidural, and oral routes.The composition may be administered by any convenient route, for exampleby infusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa,etc.) and may be administered together with other biologically activeagents. Administration can be systemic or local.

Pharmacological preparations for oral use can be made using a solidexcipient, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose,and/or physiologically acceptable polymers such as polyvinylpyrrolidone(PVP). If desired, disintegrating agents may be added, such ascross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures.

The injectable preparations may include dosage forms for intravenous,subcutaneous, intracutaneous and intramuscular injections, localinjection, drip infusions, etc. These injectable preparations may beprepared by methods publicly known. For example, the injectablepreparations may be prepared, e.g., by dissolving, suspending oremulsifying the pharmaceutical composition or dosage form in a sterileaqueous medium or an oily medium conventionally used for injections. Asthe aqueous medium for injections, there are, for example, physiologicalsaline, an isotonic solution containing glucose and other auxiliaryagents, etc., which may be used in combination with an appropriatesolubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol(e.g., propylene glycol, polyethylene glycol), a nonionic surfactant[e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct ofhydrogenated castor oil)], etc. As the oily medium, there are employed,e.g., sesame oil, soybean oil, etc., which may be used in combinationwith a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc.The injection thus prepared can be filled in an appropriate ampoule.

Pharmaceutical compositions, which can be used orally, include push-fitcapsules made of gelatin as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In soft capsules, theactive components may be dissolved or suspended in suitable liquids,such as fatty oils, liquid paraffin, or liquid polyethylene glycols.

Alternatively, the composition may be in a powder form for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.The exact formulation, route of administration and dosage may be chosenby the physician familiar with the patient's condition. (See for exampleFingl, et al., 1975, in “The Pharmacological Basis of Therapeutics”,Chapter I, p. 1). Depending on the severity and responsiveness of thecondition treated, dosing can also be a single administration of a slowrelease composition, with course of treatment lasting from several daysto several weeks or until cure is effected or diminution of the diseasestate is achieved.

Advantageously, the pharmaceutical compositions for oral or parenteraluse described above are prepared into dosage forms in a unit dose suitedto fit a dose of the active ingredients. Such dosage forms in a unitdose include, for example, tablets, pills, capsules, injections(ampoules), suppositories, chews, pet food, etc. In certain embodiments,for the dosages provided above, they are administered in one serving ofpet food, e.g. 1 mg/kg of hemp extract provided in one serving of petfood.

In accordance with the methods disclosed herein, pharmaceuticalformulations can be administered to the patient using any acceptabledevice or mechanism. For example, the administration can be accomplishedusing a syringe and needle or with a reusable pen and/or autoinjectordelivery device. The methods of the present invention include the use ofnumerous reusable pen and/or autoinjector delivery devices to administera pharmaceutical formulation.

In an embodiment for non-human animal administration, the term“pharmaceutical” as used herein may be replaced by “veterinary.”

EXAMPLES Example 1: CBD Oil and Protocols Approval

The industrial hemp strain used in this study was a proprietary hempstrain utilizing ethanol and heat extraction with the final desiccatedproduct reconstituted into an olive oil base containing approximately 10mg/ml of CBD as an equal mix of CBD and carboxylic acid of CBD (CBDa),0.24 mg/ml tetrahydrocannabinol (THC), 0.27 mg/ml cannabichromene (CBC),and 0.11 mg/ml cannabigerol (CBG) which is dehydrated; all othercannabinoids were less than 0.01 mg/ml. Analysis of 5 differentproduction runs using a commercial analytical laboratory (MCRLaboratories, Framingham, Mass.) show less than a 9% difference acrossbatches for each of the detected cannabinoids listed above. The studywas performed after the Cornell University institutional animal care anduse committee (IACUC) approved the study which follows the guidelinesfor animal use according to the IACUC. Client owned dogs were enrolledafter informed consent in accordance with the Declaration of Helsinki.

Example 2: Terpene Profiles

Terpene profiles were examined for four separate oil extractions,prepared as described above. All oils contained 0.09-0.13% α-pinene,0.23-0.44% β-myrcene, 0.04-0.09% β-pinene, 0.05-0.09% δ-limonene,0.03-0.06% linalool, 0.04-0.07% β-caryophyllene, 0.02-0.04% α-humulene,0.04-0.07% nerolidol 2, 0.02-0.04% guaiol, 0.04-0.08% caryophylleneoxide, and 0.01-0.04% α-bisabolol. In addition, some of the oils testedcontained 0.02% camphene, 0.02-0.03% β-ocimene, 0.02-0.05% eucalyptol,0.02% isopulegol, and/or 0.02-0.04% nerolidol 1. Total terpenes rangedfrom 0.73-1.10%,

Example 3: Pharmacokinetics

An initial investigation into single-dose oral pharmacokinetics wasperformed with 4 beagles (3.5-7 years, male castrated, 10.7-11.9 kg).Each dog received a 2 mg/kg and an 8 mg/kg oral dosage of CBD oil, witha 2-week washout period between each experiment. The dogs were fed twohours after dosing. Physical examination was performed at 0, 4, 8 and 24hours after dosing. Attitude, behavior, proprioception, and gait weresubjectively evaluated at each time point during free running/walkingand navigation around standard traffic cones (weaving). Five ml of bloodwas collected at time 0, 0.5, 1, 2, 4, 8, 12 and 24 hours after oiladministration. Blood samples were obtained via jugular venipuncture andtransferred to a coagulation tube for 20 minutes. Samples werecentrifuged (VWR, Clinical Centrifuge) at 3,600×g for 10 minutes; serumwas removed and stored at −80° C. until analysis using liquidchromatography-mass spectrometry (LC-MS) at Colorado State UniversityCore Mass Spectrometry facility.

Example 4: Extraction of CBD from Canine Serum and Mass SpectrometryAnalysis

CBD was extracted from canine serum using a combination of proteinprecipitation and liquid-liquid extraction using n-hexane, with minormodifications for microflow ultra-high pressure liquid chromatography(UHPLC). Briefly, 0.05 ml of canine serum was subjected to proteinprecipitation in the presence of ice-cold acetonitrile (80% finalconcentration), spiked with deuterated CBD as the internal standard(0.06 mg/ml, CDB-d₃ Cerilliant, Round Rock, Tex., USA). 0.2 ml of waterwas added to each sample prior to the addition of 1.0 ml of hexane toenhance liquid-liquid phase separation. Hexane extract was removed andconcentrated to dryness under laboratory nitrogen. Prior to LC-MSanalysis, samples were resuspended in 0.06 mL of 100% acetonitrile. Astandard curve using the CBD analytical standard was prepared in canineserum non-exposed to CBD and extracted as above. Cannabidiolconcentration in serum was quantified using a chromatographicallycoupled triple-quadropole mass spectrometer (UHPLC-QQQ-MS).

Example 5: CBD Serum Concentration Data Analysis

From the UHPLC-QQQ-MS data, peak areas were extracted for CBD detectedin biological samples and normalized to the peak area of the internalstandard CBD-d₃, in each sample using Skyline as well as an in-house RScript (www.r-project.org). CBD concentrations were calculated tonanograms per mL of serum as determined by the line of regression of thestandard curve (r2=0.9994, 0−1000 ng/mL). For this assay, the limits ofdetection (LOD) and limits of quantification (LOQ) represent the lowerlimits of detection and quantification for each compound in the matrixof this study. Pharmacokinetic variables were estimated by means ofnon-compartmental analysis, utilizing a pharmacokinetic software package(PK Solution, version 2.0, Montrose, Colo., USA).

Example 6: Inclusion and Exclusion Criteria for Clinical Trial

The study population consisted of client-owned dogs presenting toCornell University Hospital for Animals for evaluation and treatment ofa lameness due to OA. Dogs were considered for inclusion in the study ifthey had radiographic evidence of OA, signs of pain according toassessment by their owners, detectable lameness on visual gaitassessment and painful joint(s) on palpation. Each dog had an initialcomplete blood count ([CBC] Bayer Advia 120, Siemens Corp., New York,N.Y., USA) and serum chemistry analysis (Hitachi 911, Roche Diagnostics,Indianapolis, Ind., USA) performed to rule out any underlying diseasethat might preclude enrolment. Elevations in alkaline phosphatase (ALP),alanine aminotransferase (ALT) and aspartate aminotransferase (AST) wereallowed if prior hepatic ultrasound was deemed within normal limitsexcept for potential non-progressive nodules (possible hepatic nodularhyperplasia).

All owners completed a brief questionnaire to define the affectedlimb(s), duration of lameness, and duration of analgesic or othermedications taken.

All dogs underwent radiographic examination of affected joints and aradiologist confirmed the presence or absence of OA, and excluded thepresence of concomitant disease that might preclude them from enrolment(i.e. lytic lesions).

During the trial, dogs were only allowed to receive NSAIDs, fish oil,and/or glucosamine/chondroitin sulphate without any change in thesemedications for 4 weeks prior to or during the 10-week study period asstandard of care for the disease process. Other analgesic medicationsused, such as gabapentin and tramadol, were discontinued at least 2weeks prior to enrollment. Dogs were excluded if they had evidence ofrenal, uncontrolled endocrine, neurologic, or neoplastic disease, or ifthey had a temperament not suited for gaiting on a lead or wereundergoing physical therapy. Every dog was fed its regular diet with nochange allowed during the trial.

Example 7: Clinical Trial

The study was a placebo-controlled, double-blind, cross-over clinicaltrial. Dogs received each of two treatments in random order (RandomizeriPhone Application): CBD, 2 mg/kg every 12 hours, or placebo (anequivalent volume of olive oil with 10 parts per thousands of anise oiland 5 parts per thousands of peppermint oil to provide a similar herbalsmell) every 12 hours. Each treatment was administered for 4 weeks witha 2-week washout period in between treatments. Blood was collected torepeat complete blood counts and chemistry analysis at weeks 2 and 4 foreach treatment.

At each visit, each dog was evaluated by a veterinarian based on ascoring system, as well as by its owner (canine brief pain inventory[CBPI], Hudson activity scale) before treatment initiation and at weeks2 and 4 thereafter.

Example 8: Statistical Analysis

Initial power analysis was performed to assess number of dogs needed forthis study as a cross over design with a power set 0.80 and alpha of0.05 using prior data suggesting a baseline CBPI or Hudson score changeof approximately 15 points (two tailed) with a standard deviation of 20.When calculated it was assumed that 14 dogs would be necessary to findsignificance.

Statistical analysis was performed with a commercially availablesoftware package (JMP 12.0, Cary, N.C., USA). All data was assessedutilizing a Shapiro-Wilks test for normality. Considering a majority ofour blood, serum and scoring data was normally distributed a mixed modelanalysis of variance was used. Cross-over study variables included inthe model were: fixed effects of treatment, time, sequence of oil,gender, age, NSAID usage, treatment×time; as well as random effects ofobservation period, period nested within dog, time point nested withinperiod nested within dog. To control for difference and relative changein CBPI pain and activity interference assessments and Hudson scoringacross dogs, the fixed effect of initial CPBI or Hudson Score was alsoincluded for these analyses. Dunnett's tests were performed post hoc onany significant effects of time×treatment to assess differences withweek 0 of CBD oil or placebo oil as the baseline time point forcomparison. A p value of less than 0.05 was determined to be significantfor all analyses.

Example 9: Pharmacokinetic Results

Pharmacokinetics demonstrated that CBD half-life of elimination medianwas 4.2 hours (3.8-6.8 hours) with the 2 mg/kg dose, and 4.2 hours(3.8-4.8 hours) with the 8 mg/kg dose (Table 1). Median maximalconcentration of CBD oil (FIG. 2 ) was 102.3 mg/ml (60.7-132.0 ng/mL;180 nM) and 590.8 ng/mL (389.5-904.5 ng/mL; 1.2 uM) and was reachedafter 1.5 hours and 2 hours, respectively, for 2 and 8 mg/kg doses. Noobvious psychoactive properties were observed on evaluation at any timepoint during the 2 and 8 mg/kg doses over 24 hours. These results led toa practical dosing during the clinical trial of 2 mg/kg body weightevery 12 hours.

TABLE 1 Serum pharmacokinetic of 2 mg/kg and 8 mg/kg oral dosage of CBDoil medians and ranges after 2 mg/kg and 8 mg/kg single oral dosing CmaxTmax T½ elim AUD 0-t MRT (ng/ml) (h) (h) (ng-hr/ml) (h) Dose (2 mg/kg)Dog 1  60.7 1 4.4  183   6   Dog 2 132   1 3.9  351   4.2 Dog 3 102.7 23.8  382   5.1 Dog 4 101 9 2 6.8  437   9.1 Median 102 3 1.5 4 2  367.25.6 (Range) (60.7- (1.0- (3.8- (183.5- (4.2- 132.0) 2 0) 6.8) 437.4)9.1) Dose (8 mg/kg) Dog 1 499   2 3.8 2928   5 7 Dog 2 389   1 4.81753   7   Dog 3 904   2 4.2 3048   5.1 Dog 4 682   2 4.1 2389   5.2Median 590 8 2.0 4.2 2658.6 5.2 (Range) (389.5- (1.0- (3.8- (1753.6-(5.1- 904.5) 2.0) 4.8) 3048 6) 7.0) Legend: Cmax = maximumconcentration; Tmax = time of maximum concentration; T½ el = half-lifeof elimination; AUC 0-t = area under the curve (time 0 to 24 h); MRT =median residence time.

Example 10: Dogs Included in Clinical Trial

Twenty-two client-owned dogs with clinically and radiographicallyconfirmed evidence of osteoarthritis were recruited. Sixteen of thesedogs completed the trial and were included in the analyses; their breed,weight, age, sex, worse affected limb, radiographic findings, use ofNSAIDs and sequence of treatments are summarized in Table 2. Dogs wereremoved due to osteosarcoma at the time of enrolment, gastric torsion(placebo), prior aggression issues (CBD oil), pyelonephritis/kidneyinsufficiency (CBD oil), recurrent pododermatitis (placebo oil), anddiarrhea (placebo oil).

TABLE 2 Characteristics (breed, weight, age, sex, affected limbs,radiographic findings, concomitant utilization of NSAID and sequence oftreatment) of the dogs included in this study. Weight Age Worse Breed(kg) (years) Sex limb Radiographic findings and OA localization NSAIDRottweiler 35.3 10

Moderate inttracapsules 

 with moderate 

( 

 kg BID) Mix

13 MC RF Moderate-to-severe. right- 

 left-shoulder 

No Moderate-to-severe 

 hip 

Mix

9

LF Moderate med 

 remodeling (with 

No on the right and 

Mix 30.5 14 MC Moderate enth 

 on right 

 left- 

No

 moderate 

Mix 23.5 10 FS Moderate 

 and moder 

(2.2 mg/kg) Mix 28.3 10 FS LF Moderate 

 elbow 

Meta 

Moderate left- 

 with 

 swelling (0.1 mg/kg) English 25.2 8 MC LF Severe 

 left elbow Verprofen Bulldog Moderate 

 swelling and mild 

 right 

(2.0 mg/kg BID) German 21.5 14 FS RB Moderate 

 elbow 

Shorthaired (2.4 mg/kg) Pointer Lab 

26.1 13 FS Bilateral severe 

 due to 

 disease Mer 

Retriever (0.1 mg.kg BID) Mix 18.2 13 FS RF Bilateral moderate elbow 

  Meta 

(0.1 mg/kg BID) Mix 22 9 FS RH Moderate 

 with moderate 

 swelling No Be 

50

M RF Bilateral severe elbow 

 disease and 

Mountain (2.0 mg/kg BID) Dog Bel 

26.1 9

RF Severe bilateral elbow 

Bilateral moderate hip 

(2 mg/kg BID) Mix 25.6 13 ES Severe bilateral elbow 

No Severe bilateral hip 

Border 22 14 MC Severe 

No Collie Multi 

Beugle 17.6 5 MC Mild left elbow 

 with possible med 

 disease No Moderate-to-severe bilateral 

indicates data missing or illegible when filed

Example 11: Clinical Trial Results

CBPI and Hudson scores (FIG. 3A and FIG. 3B) showed a significantdecrease in pain and increase in activity (p<0.01) at week 2 and 4during CBD treatment when compared to baseline week 0, while placebotreatment showed no difference in CBPI and Hudson scoring from scoresprior to initiation of treatments (Table 3). Lameness as assessed byveterinarians (FIG. 4 ) showed an increase in lameness with age(p<0.01), whereas NSAID use (p=0.03) results in significantly lesslameness. Veterinary pain scores showed significantly less pain in dogson NSAIDs (p<0.01). CBD oil resulted in significantly less pain whencompared to baseline on evaluation at both week 2 and week 4 (p<0.03),while 24 placebo treatment showed no significant differences. No changeswere observed in weight-bearing capacity when evaluated utilizing theveterinary lameness and pain scoring system (Table 3).

TABLE 3 Average and standard deviation for CBPI and Hudson; median andrange for lameness, weight-bearing and pain scores at each time fortreatment and placebo oils Treatment A/CBD oil Treatment B/placebo oilWeek 0 Week 2 Week 4 Week 0 Week 2 Week 4 CBPI Pain (0-40) 21 ± 8 14 ±6* 14 ± 8* 17 ± 7 19 ± 9 19 ± 9 CBPI Interference 35 ± 15 25 ± 15* 26 ±14* 27 ± 15 29 ± 15 31 ± 16 (0-60) Hudson (0-110) 54 ± 13 67 ± 15* 67 ±10* 65 ± 14 64 ± 16 60 ± 19 Veterinary 3 (1-4) 3 (1-2) 3 (1-4) 3 (2-4) 3(2-4) 5 (1-4) lameness Veterinary pain ∫ 3 (3-4) 3 (2-4)* 3 (1-4)* 3(2-4) 3 (2-4) 3 (2-4) Veterinary 2 (1-3) 2 (1-3) 2 (1-3) 2 (1-3) 2 (1-3)2 (1-3) weight-bearing₌ Legend:Asterisk (*) represents significantdifference (p < 0.05) from baseline week 0 of CBD treatment. §Lamenesswas scored as follows; 1 = no lameness observed/walks normally, 2 =slightly lame when walking, 3 = moderately lame when walking, 4 =severely lame when walking, 5 = relucant to rise and will not walk morethan 5 paces. ∫ Pain on palpation was scored as follows: 1 = none, 2 =mild signs, dog turns head in recognition, 3 = moderate signs, dog pullslimb away, 4 = severe signs, dog vocalizes or becomes aggressive, 5 =dog will not allow palpation. =Weight-bearing was scored as follows: 1 =equal on all limbs standing and walking, 2 = normal standing, favorsaffected limb when walking, 3 = partial weight-bearing standing andwalking, 4 = partial weight-bearing standing, non-weight-bearingwalking, 5 = non-weight-bearing standing and walking.

Chemistry analysis and CBC were performed at each visit. No significantchange in the measured CBC values was noted in either the CBD oil orplacebo treated dogs (data not shown). Serum chemistry values were notdifferent between placebo compared to CBD oil (Table 4), except foralkaline phosphatase (ALP) which significantly increased over time frombaseline by week 4 of CBD oil treatment (p=0.005); with nine of thesixteen dogs showing increases over time (FIG. 1 ). Glucose wasincreased in dogs receiving the placebo oil at each time point (p=0.04)and creatinine levels increased over time in both dogs receiving CBD oiland those receiving placebo oil (p<0.01); though all values remainedwithin reference ranges. Other notable significances in serum chemistryvalues were associated with primarily age or NSAID use. An increase inage was associated with significantly higher blood urea nitrogen (BUN;p<0.001), calcium (p=0.014), phosphorus (p=0.001), alanineaminotransferase (ALT; p=0.028), ALP (p=0.012), gammaglutamyltransferase (GGT; p=0.018), globulin (p=0.021) and cholesterol(p=0.002) values. NSAID use was associated with significantly higher BUN(p=0.003), and creatinine (p=0.017), and significant decreases in totalprotein (p<0.001) and serum globulin (p<0.001).

TABLE 4 Mean + SD values for serum chemistry data obtained at each timepoint for dogs receiving CBD and placebo oilsCa Treatment A/CBD oilTreatment B/placebo oil Reference Week 0 Week 2 Week 4 Week 0 Week 2Week 4 Na 145-133 mE 

 149 ± 3  149 ± 2  149 ± 1 149 ± 

 149 ± 2  149 ± 2 K 4.1-5.6 mE 

 /L   4.9 ± 0.3  4.9 ± 0.5  4.9 ± 0.3  4.8 ± 0.4  4.9 ± 0.4  4.9 ± 0.3Cl 105-116 mE 

 /L  110 ± 3  109 ± 3  109 ± 2  110 ± 2  110 ± 2  110 ± 2 BUN 10-32 m 

 /dL 2 

 ± 9   20 ± 7   20 ± 6   19 ± 6   21 ± 7   19 ± 6 Creat 0.6-1.4 mg/dL 1.0 ± 0.3  1.1 ± 0.3*  1.0 ± 0.3*  0.9 ± 0.3  1.0 ± 0.3*  1.0 ± 0.3* Ca9.3-11.4 mg/dL 10.4 ± 0.5 10.4 ± 0.4 10.3 ± 0.4 10.4 ± 0.6 10.4 ± 0.410.4 ± 0.4 P 2.9-5.2 mg/dL  3.8 ± 0.8  3.9 ± 0.8  3.9 ± 0.6  4.0 ± 0.7 3.9 ± 0.6  4.0 ± 0.5 Mg 1.4-2.2 mg/dL  1.8 ± 0.2  1.8 ± 0.2  1.8 ± 0.2 1.8 ± 0.1  1.8 ± 0.1  1.8 ± 0.1 GLU 63-118 mg 

 L   92 ± 9   89 ± 9   92 ± 9   97 ± 10*   93 ± 8   97 ± 10* ALT 20-98 

 L   93 ± 86   95 ± 88  114 ± 119   90 ± 89  222 ± 606  166 ± 284 AST14-51 U/L   31 ± 8   33 ± 113   34 ± 16   30 ± 3   56 ± 99   45 ± 34 ALP17-111 U/L  160 ± 212  238 ± 268  323 ± 407*  204 ± 287  186 ± 287  175± 248 GGT 0-6 U/L   4 ± 3   3 ± 2   3 ± 2   3 ± 2   4 ± 6   5 ± 4 TB0.0-0.2 md/dL  0.1 ± 0.1  0.0 ± 0.1  0.1 ± 0.1  0.0 ± 0.1  0.0 ± 0.1 0.0 ± 0.1 TP 5.3-7.0 g/dL  6.3 ± 0.4  6.4 ± 0.5  6.3 ± 0.4  6.3 ± 0.4 6.3 ± 0.4  6.3 ± 0.4 ALB 3.1-4.2 g/dL  3.7 ± 0.2  3.7 ± 0.2  3.7 ± 0.2 3.7 ± 0.2  3.7 ± 0.2  3.7 ± 0.2 GLOB 1.9-5.6 g/dL  2.6 ± 0.3  2.6 ± 0.4 2.6 ± 0.4  2.6 ± 0.4  2.6 ± 0.4  2.6 ± 0.4 CHOL 138-332 mg/dL  291 ± 64 301 ± 62  502 ± 62  295 ± 71  300 ± 71  308 ± 83 CK 48-260 U/L  148 ±81  147 ± 59  134 ± 61  139 ± 57  188 ± 80  168 ± 10 Legend: Asterisk(*) indicates significantly different (p < 0.05) serum concentrationfrom baseline week 0 CBD treatment.

indicates data missing or illegible when filed

Example 12: Canine Safety Study

A 12-week safety study was performed in canines to evaluate the safetyof a soft chew containing CBD.

Animals and Study Design

Eight purebred beagle dogs, 11 months-5 years old, weighing 7.39-11.95kg at study start were selected for the study, as shown in Table 5.

TABLE 5 Animal information Dog ID Sex Date of Birth 13536 F Dec. 24,2013 2753822 F Jan. 4, 2015 2808987 F Mar. 8, 2015 13644 M Feb. 7, 20172784123 M Feb. 8, 2015 2963028 M Sep. 12, 2015 13513 F Jul. 31, 201313490 M Nov. 1, 2012

Dogs were single housed in cages of a size in accordance with the AnimalWelfare Act, with a 12-hour-light/12-hour-dark cycle and targetedconditions of 50° to 85° F. Cages and food bowls were cleaned daily andsanitized in accordance with the Animal Welfare Act. Fresh tap water,fit for human consumption, was available ad libitum by means of anautomatic watering system. There were no known contaminants that werereasonably expected to be present in the dietary material that wereknown to be capable of interfering with the purpose or conduct of thestudy.

During the study, the control diet, Purina Dog Chow, was the sole sourceof food supplied to each animal once daily for approximately 1 hour.Dogs were fed according to ideal body condition and fasted for a minimumof 12 hours prior to blood collections. CBD was administered by a softchew offered twice daily at the approximate dosage of 2 mg/kg. Dosing isshown in Table 6.

TABLE 6 Quantity of chews offered per week Week Dog ID Sex 1 2 3 4 5 613536 F 2 small 1 large. 1 large. 1 large, 1 large, 1 large, 1 small 1small 1 small 1 small 1 small 2753822 F 1 large 1 large 1 large 1 large1 large 1 large 2808987 F 2 small 2 small 2 small 2 small 1 large, 1large 1/2 small 1/2 small 13044 M 1 large 1 large 1 large 1 large 1large 1 large 1/2 small 1/2 small 1/2 small 1/2 small 1/2 small 1/2small 2784123 M 1 large 1 large 1 large 1 large 1 large 1 large 1/2small 1/2 small 1/2 small 1/2 small 1/2 small 1/2 small 2963028 M 1large 1 large 1 large 1 large 1 large 1 large 1/2 small 1/2 small 1/2small 1/2 small 1/2 small 1/2 small 13523 F 1 large 1 large 1 large 1large 1 large 1 large 1/2 small 1/2 small 1/2 small 1/2 small 1/2 small1/2 small 13490 M 2 small 2 small 2 small 1 large 1 large 1 large 1/2small 1/2 small 1/2 small Week Dog ID Sex 7 8 9 10 11 12 13536 F 1large, 1 large, 1 large, 1 large, 1 large, 1 large, 1 small 1 small 1small 1 small 1 small 1 small 2753822 F 1 large 1 large 1 large 1 large1 large 1 large 2808987 F 1 large, 1 large, 1 large, 1 large, 1 large, 1large, 1/2 small 1/2 small 1/2 small 1/2 small 1/2 small 1/2 small 13044M 1 large, 1 large, 1 large, 1 large, 1 large, 1 large, 1/2 small 1/2small 1/2 small 1/2 small 1/2 small 1/2 small 2784123 M 1 large, 1large, 1 large, 1 large, 1 large, 1 large, 1/2 small 1/2 small 1/2 small1/2 small 1/2 small 1/2 small 2963028 M 1 large, 1 large, 1 large, 1large, 1 large, 1 large, 1/2 small 1/2 small 1/2 small 1/2 small 1/2small 1/2 small 13523 F 1 large, 1 large, 1 large, 1 large, 1 large, 1large, 1/2 small 1/2 small 1/2 small 1/2 small 1/2 small 1/2 small 13490M 1 large, 1 large, 1 large, 1 large, 1 large, 2 small 1/2 small 1/2small 1/2 small 1/2 small 1/2 small

CBC and Serum Chemistry

Prior to study initiation, 5 milliliters of blood was collected for eachdog and was used to determine eligibility for the study. During thestudy, 5 milliliters of blood was collected weekly (±2 days). Blood wascollected via jugular venipuncture in sterile syringes. Samples weresplit into two tubes: a red-top serum separator tube and a lavender-topEDTA tube. Red-top tubes were spun in a refrigerated centrifuge for 15minutes at 3000 RPM after being allowed to clot. Lavender-top tubes wereplaced on a rocker to allow the blood to adequately mix with theanticoagulant. Blood samples were packaged and sent bypriority-overnight to Antech Diagnostics for analysis.

Pharmacokinetic (PK) Blood Collection

On the first day of dosing, blood was collected for a PK analysis from 6of the 8 dogs. The most cooperative dogs were selected for the PKanalysis. Approximately 6 milliliters of blood was collected via jugularvenipuncture in sterile syringes at 0 min, 30 min, 60 min, 2 hrs, 4 hrs,8 hrs, 12 hrs, and 24 hrs after treatment. Samples were placed into redtop clotting tubes with no serum separator. Serum was harvested bycentrifuging the tubes at 3000 RPM for 15 minutes. The harvested serumwas placed in cyrovials and stored at −70° C. Each tube was labeled withthe dog id, date of collection, and collection time point. Samples wereshipped overnight on dry ice to the Proteomics & Metabolomics Facilityat the Colorado State University.

Clinical Observations

A veterinarian performed a complete physical examination of all dogsprior to the initiation of the study and at study completion. Each dogwas evaluated as to general health, body and hair coat condition.Qualified personnel performed clinical observations twice daily inaccordance with Summit Ridge Farms' Program of Veterinary Care and SOPVC-003 (Rounds Observations). All animals were evaluated twice dailywith reference to SOP VC-016 (Recognizing Pain, Stress and/or Distress).Clinical laboratory diagnostic procedures were performed as needed.Veterinary care was given as appropriate to each individual animal inaccordance with the Program of Veterinary Care.

Blood Analysis

Blood was analyzed for white blood cell count, red blood cell count,hemoglobin, hematocrit, MCV, MCHC, MCH, and platelet count along with acomplete differential. In addition, a 22-test chemistry screen wasperformed consisting of Glucose, Urea Nitrogen, Creatinine, TotalProtein, Albumin, Total Bilirubin, Alkaline Phosphatase, ALT, AST, CPK,Cholesterol, Calcium, Phosphorus, Sodium, Potassium, Chloride, A/GRatio, BUN/Creatinine Ratio, Globulin, Triglycerides, GGTP andMagnesium. Measurements were taken prior to the start of the study andthen weekly during the course of the study.

PK Analysis

Analysis of the blood level values and pharmacokinetics of the testarticle were performed.

Results Body Weight

The mean average weight change for dogs during the 12 weeks of the studywas −0.04 kg (−0.43%). Weight data is presented in Tables 7 and 8.

TABLE 7 Weekly body weights (weeks 1-6) Week Dog ID Sex Base 1 2 3 4 5 613536 F 11.95 12.34 11.95 12.10 12.05 12.08 12,04 2753822 F 7.30 7.247.18 7.16 7.03 6.99 7.03 2808987 F 10.40 10.40 10.36 10.23 10.1 6 10.2110.20 13644 M 8.92 9.25 9.56 9.65 9.63 9.50 9.64 2784123 M 9.21 8.939.07 9.27 9.18 9.13 9.33 2963028 M 9.28 9.15 9.13 8.98 9.07 9.32 9.2813513 F 9.67 9.58 9.52 9.16 9.10 9 14 8.78 13490 M 10.58 10.64 10.4510.39 10.27 10.39 10.28 Mean 9.68 9.69 9.65 9.62 9.56 9.50 9.57 SD 1.3461.488 1.371 1.410 1418 1,438 1.425

TABLE 8 Weekly body weights (weeks 7-12) Week Dog ID Sex 7 8 9 10 11 12Chg. % Chg. 13536 F 12.09 11.99 12.04 12.09 12.10 11.97 0.02 0.172753822 F 7.17 7.04 7.23 7.41 7.28 7.34 −0.05 −0.68 2808987 F 10.32 9.989.90 9.98 9.95 10.15 −0.25 −2.40 13644 M 9.53 9.49 9.28 9.42 9.28 9.120.20 2.34 2784123 M 9.46 9.58 9.47 9.67 9.39 9.18 −0.03 −0.33 2963028 M9.32 9.26 9.23 9.51 9.66 9.55 0.27 2.91 13513 F 9.09 9.58 9.15 8.88 8.818.89 −0.78 −8.07 13490 M 10.42 11.06 10.98 10.90 11.06 10.87 0.29 2 74Mean: 9.68 9.75 9.66 9.73 9.69 9.63 −0.04 −0.43 SD. 1.395 1.439 1.4141.326 1.444 1.391 0.350 3.605

Food Consumption

The mean daily food consumption per week for dogs during the study was204 g. Food consumption data is presented in Tables 9 and 10.

TABLE 9 Average daily food consumption per week (weeks 1-6) Week Dog IDSex 1 2 3 4 5 6 13536 F 250 207 200 200 200 177 2753822 F 144 162 176157 154 186 2808987 F 203 223 212 184 209 235 13644 M 285 300 275 250229 225 2784123 M 300 300 300 300 300 300 2963028 M 137 150 150 192 173160 13513 F 149 128 146 157 145 127 13490 M 190 246 253 143 144 166Mean: 207 215 214 198 194 197 SD: 64.5 65.6 57.4 53.1 52.9 54.1

TABLE 10 Average daily food consumption per week (weeks 7-12) Week DogID Sex 7 8 9 10 11 12 Avg 13536 F 200 200 200 200 200 182 201 2753822 F208 145 160 207 202 242 179 2808987 F 231 197 203 222 194 217 211 13644M 200 200 200 200 190 190 229 2784123 M 300 300 275 275 165 165 2732963028 M 200 190 179 199 226 185 179 13513 F 205 280 143 104 168 191162 13490 M 191 266 193 214 215 210 203 Mean: 217 222 194 203 195 198204 SD: 35.5 53.3 39.1 47.1 20.9 24.0 34.9

Test Article Consumption

Five of the eight dogs had 100% acceptance of the chews. Three dogs hadto be dosed on occasion during the study: Dog ID #13644 (dosed 6.5% ofthe time), Dog ID #13513 (dosed 2.4% of the time) and Dog ID #2784123(dosed 17.3% of the time).

Hematology and Serum Chemistry

Beginning in Week 1, there was a slight increase mean alkalinephosphatase (ALP) value for the group. This value remained stable untilWeek 7 when the group mean ALP value became increasingly elevated. Thehighest group mean value was observed during the final week of thestudy, but did not exceed the normal reference range, shown in Table 11.The cause of the group mean value elevations appeared to be due to threedogs (13536, 2753822 and 2808987). By the end of the study 13536 and2753822 were above 100 U/L, but did not exceed the normal high of 131U/L. Thus, their levels remained within the normal reference range. Theobserved elevations in only a few animals in the group may indicateindividual sensitivity to the product. All other blood parametersremained within normal limits and no apparent trends were noted.Hematology and serum chemistry results are presented in Tables 12-19.

TABLE 11 Hematology and serum chemistry normal reference rangesParameter Normal Reference Ranges Total Protein (g/dL): 5.0-7.4 g/dLAlbumin (g/dL): 2.7-4.4 g/dL Globutin (g/dL): 1.6-3.6 g/dL A/G Ratio:0.8-2.0 Ratio AST (U/L): 15-66 U/L ALT (U/L): 12-118 U/L AlkalinePhosphatase (U/L): 5-131 U/L GGTP (U/L): 1-12 U/L Total Bilirubin(mg/dL): 0.1-0.3 mg/dL Urea Nitrogen (mg/dL): 6-31 mg/dL Creatinine(mg/dL): 0.5-1.6 mg/dL BUN/Creatinine Ratio: 4-27 Ratio Phophorus(mg/dL): 2.5-6.0 mg/dL Glucose (mg/dL): 70-138 mg/dL Calcium (mg/dL):8.9-11.4 mg/dL Magnesium (mEq/L): 1.5-2.5 mEq/L Sodium (mEq/L): 139-154mEq/L Potassium (mEq/L): 3.6-5.5 mEq/L Chloride (mEq/L): 102-120 mEq/LCholesteral (mg/dL): 92-324 mg/dL Triglycerides (mg/dL): 29-291 mg/dLCPK (U/L): 59-895 U/L WBC(10{circumflex over ( )}3/mm3): 4.0-15.510{circumflex over ( )}3/mm3 RBC(10{circumflex over ( )}6/mm3): 4.8-9.310{circumflex over ( )}3/mm3 Hemoglobin (g/dL): 12.1-20.3 g/dLHematocrit (%): 36-60% MCV (um{circumflex over ( )}3): 58-70um{circumflex over ( )}3 MCH (

g): 19-28

g MCHC (g/dL): 30-38 g/dL Platelets (10{circumflex over ( )}3/mm3):170-400 10{circumflex over ( )}3/mm3 Absolue Polys:  2060-10600 AbsoluteBands:  0-300 Absolute Lymphs:  690-4500 Absolute Monos:  0-840 AbsoluteEos:   0-1200 Absolute Basos:  0-150

indicates data missing or illegible when filed

TABLE 12 Summary of hematology and serum chemistry results (weeks 0-5) -Part 1 Total Alkaline Total Urea Protein Albumin Globulin A/G AST ALTPhosphatase GGTP Billrubin Nitrogen Creatinine (g/dL) (g/dL) (g/dL)Ratio (U/L) (U/L) (U/L) (U/L) (mg/dL) (mg/dL) (mg/dL) Initial ResultsMean: 6.

3.5 2.6 1.4 27 34 39 4 0.1 11 0.5 SD:

.30 0.22 0.33 0.21 6.9 7.6 16.1 0.5 0.04 2.1 0.07 N: 8 8 8 8 8 8 8 8 8 88 Week 1 Mean: 6.2 3.5 2.7

.3 26 29 46 4 0.1 11 0.5 SD: 0.34 0.25 0.43 0.24 5.7 5.8 26.7 1.3 0.002.4 0.09 N: 8 8 8 8 8 8 8 8 8 8 8 Week 2 Mean: 6.0 3.5 2.5 1.4 26 30 493 0.1 10 0.5 SD: 0.49 0.24 0.48 0.29 5.9 5.7 23.8 0.5 0.00 1.6 0.06 N: 88 8 8 8 8 8 8 8 8 8 Week 3 Mean: 6.2 3.4 2.7 1.3 25 28 48 3 0.1 10 0.5SD: 0.43 0.23 0.40 0.18 6.0

.4 19.6 0.5 0.0

1.8 0.06 N: 8 8 8 8 8 8 8 8 8 8 8 Week 4 Mean: 5.9 3.5 2.5 1.5 25 27 463 0.1 10 0.5 SD: 0.45 0.23 0.40 0.24 7.0 5.

21.0 0.9 0.00 1.6 0.05 N: 8 8 8 8 8 8 8 8 8 8 8 Week 5 6.2

.5 2.8 1.3 25 29 48

0.1 10 0.6 0.42 0.24 0.42 0.21 5.7 6.3 22.0 0.6 0.04 1.9 0.09 8 8 8 8 88 8 8 8 8 8

indicates data missing or illegible when filed

TABLE 13 Summary of hematology and serum chemistry results (weeks6-10) - Part 1 Total Alkaline Total Urea Protein Albumin Globulin A/GAST ALT Phosphatase GGTP Billrubin Nitrogen Creatinine (g/dL) (g/dL)(g/dL) Ratio (U/L) (U/L) (U/L) (U/L) (mg/dL) (mg/dL) (mg/dL) Week 6Mean: 6.0 3.4 2.6 1.4 24 29 47 4 0.1 10 0.5 SD: 0.41 0.24 0.42 0.25 5.86.4 23.0 0.4 0.0

1.5 0.07 N: 8 8 8 8 8 8 8 8 8 8 8 Week 7 Mean: 6.4 3.6 2.8 1.3 25 32 544 0.1 10 0.6 SD: 0.41

.32 0.35 0.21 6.2 8.3 25.6 0.7 0.00 1.5 0.11 N: 8 8 8 8 8 8 8 8 8 8 8Week 8 Mean: 6.3 3.5 2.9 1.2 23 35 36 4 0.1 11 0.5 SD: 0.45 0.28 0.410.18 4.5 28.2 23.3 0.5 0.00 2.8 0.08 N: 8 8 8 8 8 8 8 8 8 8 8 Week 9Mean: 6.2 3.6 2.6 1.4 25 31 55 5 0.2 11 0.6 SD:

.39 0.20 0.41 0.22 4.2 8.8 29.2 0.8 0.05 1.8 0.10 N: 8 8 8 8 8 8 8 8 8 88 Week 10 Mean: 6.1 3.5 2.6 1.4 24 29 56 4 0.1 11 0.5 SD: 0.42 0.22 0.430.26 5.0 7.0 32.7 0.6 0.00 1.7 0.08 N: 8 8 8 8 8 8 8 8 8 8 8 Week 11Mean: 6.0 3.4 2.6 1.4 25 28 61 4 0.1 11 0.5 SD: 0.48 0.23 0.46 0.26 4.27.3 35.7 1.1 0.05 1.1 0.11 N: 8 8 8 8 8 8 8 8 8 8 8

indicates data missing or illegible when filed

TABLE 14 Summary of hematology and serum chemistry results (weeks 0-5) -Part 2

UN/ Creatinine Phosphorus Glucose Calcium Magnesium Sodium PotassiumChloride Cholesterol Triglycerides Ratio (mg/dL) (mg/dL) (mg/dL) (mEq/L)(mEq/L) (mEq/L) (mEq/L) (mg/dL) (mg/dL) Initial Results Mean: 21 4.3 9710.4 1.6 148 4.3 113 182 48 SD: 2.7 0.62 9.4 0.33 0.13 1.2 0.35 0.9 36.511.1 N: 8 8 8 8 8 8 8 8 8 8 Week 1 Mean: 21 4.2 95 10.5 1.6 147 4.4 112188 45 SD: 3.0 0.89 6.6 0.31 0.0

0.6 0.25 1.6 45.5 1

.8 N: 8 8 8 8 8 8 8 8 8 8 Week 2 Mean: 20 4.0 93 10.4 1.5 147

.5 111 191 47 SD: 2.7 0.78 6.4 0.28 0.13 1.6 0.33 1.6 43.8 12.8 N: 8 8 88 8 8 8 8 8 8 Week 3 Mean: 20 4.2 102 10.5 1.6 150 4.0 113 200 43 SD:4.1 0.

6.0 0.39 0.0

1.8 0.26 2.2 33.4 9.1 N: 8 8 8 8 8 8 8 8 8 8 Week 4 Mean: 20 4.1 92 10.01.6 148 4.4 113 203 44 SD: 2.0 0.64 6.5 0.32 0.08 1.1 0.37 1.5 33.4 10.7N: 8 8 8 8 8 8 8 8 8 8 Week 5 Mean: 18 3.9 96 10.3 1.5 14

4.

112 206 43 SD: 2.1 0.54 7.7 0.25 0.07 1.4 0.27 1.6 30.8 12.2 N: 8 8 8 88 8 8 8 8 8

indicates data missing or illegible when filed

TABLE 15 Summary of hematology and serum chemistry results (weeks6-10) - Part 2

UN/ Creatinine Phosphorus Glucose Calcium Magnesium Sodium PotassiumChloride Cholesterol Triglycerides Ratio (mg/dL) (mg/dL) (mg/dL) (mEq/L)(mEq/L) (mEq/L) (mEq/L) (mg/dL) (mg/dL) Week 6 Mean: 2

3.9 91 10.0 1.5 147 4.4 112 191 44 SD: 1.8 0.48 6.3 0.27

.09 0.7 0.10 2.6 31.5 13.1 N: 8 8 8 8 8 8 8 8 8 8 Week 7 Mean: 18 4.1 9610.0 1.6 149 4.4 112 197 48 SD: 2.9

.50 8.0 0.38 0.12 2.0 0.27 1.2 31.3 12.3 N: 8 8 8 8 8 8 8 8 8 8 Week 8Mean: 22 4.2 102 10.2 1.6 146 4.3 111 211 43 SD: 6.9 0.92 7.9 0.35 0.102.2 0.21 1.6 33.7 12.9 N: 8 8 8 8 8 8 8 8 8 8 Week 9 Mean: 20 3.8 10010.

1.5 149 4.5 114 20

44 SD: 3.5

.71 8.5 0.33

.12 1.2 0.29 1.5 34.1 11.5 N: 8 8 8 8 8 8 8 8 8 8 Week 10 Mean: 22 4.394 10.3 1.6 149 4.4 113 206 46 SD: 2.8 0.81 9.2 0.25 0.11 0.5 0.26 1.741.3 12.4 N: 8 8 8 8 8 8 8 8 8 8 Final Results Mean: 22 4.0 99 10.1 1.6148 4.2 113 212 46 SD: 3.9 0.68 6.4 0.34 0.12 1.2 0.14 3.0 49.2 15.8 N:8 8 8 8 8 8 8 8 8 8

indicates data missing or illegible when filed

TABLE 16 Summary of hematology and serum chemistry results (weeks 0-5) -Part 3 CPK WBC RBC Hemoglobin Hematocrit MCV MC

MCHC Platelets (U/L) (10{circumflex over ( )}3/mm3) (10{circumflex over( )}6/mm3) (g/dL) (%) (um

3) (

g) (g/d

) (10{circumflex over ( )}3/mm3) Initial Results Mean: 130 8.4 7.5 17.554 72 23.5 33 318 SD: 45.2 2.06 0.72 1.67 4.1 2.4 0.80 1.0 50.7 N: 8 8 88 8 8 8 8 8 Week 1 Mean: 95 9.8 7.1 16.6 52 73 23.3 32 312 SD: 12.6 2.390.37 0.86 2.5 2.1 0.58 0.4 54.6 N: 8 8 8 8 8 8 8 8 8 Week 2 Mean: 96 8.57.5 17.0 54 72 22.8 31 318 SD: 23.5 1.63 0.37 0.60 2.1 1.9 0.59 0.7 59.8N: 8 8 8 8 8 8 8 8 8 Week 3 Mean: 81 8.7 7.4 16.8 53 72 22.7 32 306 SD:20.5 1.57 0.43 0.82 2.9 2.4 0.72 1.4 43.3 N: 8 8 8 8 8 8 8 8 8 Week 4Mean: 142 7.7 7.3 17.1 53 72 23.4 33 311 SD: 122.3 1.26 0.57 1.29 3.03.5 0.43 1.2 43.0 N: 8 8 8 8 8 8 8 8 8 Week 5 Mean: 109 8.6 7.3 17.2 5473 23.5 32 314 SD: 29.5 1.38 0.51 1.08 3.2 2.1 0.63 0.4 27.0 N: 8 8 8 88 8 8 8 8

indicates data missing or illegible when filed

TABLE 17 Summary of hematology and serum chemistry results (weeks6-10) - Part 3 CPK WBC RBC Hemoglobin Hematocrit MCV MCH MCHC Platelets(U/L) (10{circumflex over ( )}3/mm3) (10{circumflex over ( )}6/mm3)(g/dL) (%) (um

3) (

g) (g/d

) (10{circumflex over ( )}3/mm3) Week 6 Mean: 89 8.9 7.4 17.2 50 68 23.434 348 SD: 30.6 2.23 0.44 1.04 2.6 1.9 0.63 0.5 40.3 N: 8 8 8 8 8 8 8 88 Week 7 Mean: 110 7.4 7.9 17.

58 74 22.8 31 313 SD: 44.8 1.27 0.5

1.21 3.4 1.8 0.70 0.6 47.3 N: 8 8 8 8 8 8 8 8 8 Week 8 Mean: 83 7.3 7.917.9 57 73 22.7 32 304 SD: 14.4 2.56 0.36 0.56 2.2 1.7 0.76 0.5 30.6 N:8 8 8 8 8 8 8 8 8 Week 9 Mean: 83 8.4 7.8 18.1 54 70 23.2 33 321 SD:16.6 2.52 0.36 0.84 3.0 2.8 1.00 2.1 20.9 N: 8 8 8 8 8 8 8 8 8 Week 10Mean: 102 7.

7.6 17.9 56 74 23.6 32 325 SD: 22.2 1.

0.31 0.79 2.4 1.9 0.64 0.0 41.9 N: 8 8 8 8 8 8 8 8 8 Final Results Mean:97 7.7 7.5 17.8 51 69 23.7 35 347 SD: 14.5 1.91 0.3

0.82 2.1 1.9 0.71 0.5 54.3 N: 8 8 8 8 8 8 8 8 8

indicates data missing or illegible when filed

TABLE 18 Summary of hematology and serum chemistry results (weeks 0-5) -Part 4 Abs Polys % Polys Abs Bands % Bands Abs Lymphs % Lymphs Abs Monos% Monos Abs Eos % Eos Abs B

%

Initial Results Mean: 5508 65 0 0 2346 28 361 5 197 2 0 0 SD: 160

.1 5.3 0.0

.0 323.3 6.0 411.8 3.2 230.6 2.4 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 8 8 Week1 Mean: 6602 67 0 0 2219 24 615 6 326 3 0 0 SD: 2065.4 6.2 0.0 0.0 323.36.0 411.8 3.2 230.6 2.4 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 2 Mean:5562 65 0 0 2223 27 370 4 308 4 0 0 SD: 1270.4 4.2 0.0 0.0 354.4 4.6113.0

.1

08.5

.9 0.0 0.

N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 3 Mean: 5877 67 0 0 2166 25 440 5 255 30 0 SD: 1235.5 3.7 0.0 0.0 450.1 3.3 92.9 1.1 82.2 1.2 0.0 0.0 N: 8 8 88 8 8 8 8 8 8 8 8 Week 4 Mean: 5216 68 0 0 1912 25 297 4 238 3 0 0 SD:1098.9 3.7 0.0 0.0 185.4 3.7 102.6 1.2 103.1 1.2 0.0 0.

N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 5 Mean: 586.4 68 0 0 2061 24 402 5 261 30 0 SD: 1124.4 4.0 0.0 0.0 410.2 5.0 178.4 1.8 112.2 1.1 0.0 0.0 N: 8 88 8 8 8 8 8 8 8 8 8

indicates data missing or illegible when filed

TABLE 19 Summary of hematology and serum chemistry results (weeks6-10) - Part 4 Abs Polys % Polys Abs Bands % Bands Abs Lymphs % LymphsAbs Monos % Monos Abs Eos % Eos Abs Basos % Basos Week 6 Mean: 5961 66 00 2281 27 400 5 286 3 0 0 SD: 1852.8 4.9 0.0 0.0 269.4 4.8 121.8 1.3204.1 1.5 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 7 Mean: 49

4 6

0 0 1918 26 32

5 209 3 0 0 SD: 1030.3 3.9 0.

.0 374.2 4.1

15.

1.4 40.6 0.6 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 8 Mean: 4889 65 0 01960 28 335 5 154 2 0 0 SD: 2096.3

.6 0.0 0.0 371.7 4.5 186.2 1.3 65.9 1.5 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 88 Week 9 Mean: 5705 67 0 0 2056 26 366 4 249 3 0 0 SD: 1967.2 4.1 0.00.0 364.1 4.

155.1 1.1 222.5 1.6 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 10 Mean:5188 66 0 0 1997 26 375 5 190 3 0 0 SD: 15

7.5 3.7 0.0 0.0 386.8 3.5 95.1 0.8 68.9 0.8 0.0 0.0 N: 8 8 8 8 8 8 8 8 88 8 8 Final Results Mean: 5221 67 0 0 1940 26 359 5 181 2 0 0 SD: 1658.65.9 0.0 0.0 453.8 77.0 197.

2.4 60.9 0.5 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 8 8

indicates data missing or illegible when filed

Clinical Observations

During the study, occasional instances of loose stool and emesis wererecorded. Dog ID #13536 was observed having five instances of food orbile emesis and six instances of loose stool. Dog ID #13513 was observedhaving two instances of loose stool. Dog ID #27583822 was observedhaving two instances of food emesis and eight instances of loose stool.Dog ID #13644 was observed having 12 instances of loose stool. Dog ID#13490 was observed having two instances of loose stool. Dog ID #2808987was observed having four instances of loose stool. Dog ID #2963028 wasobserved having six instances of loose stool. Dog ID #2784123 wasobserved having six instances of loose stool. Occasional episodes ofloose stool and bile emesis are not unusual in the dog colony and werenot considered to be related to the test article. Clinical observationsare listed in Table 20.

TABLE 20 Clinical observations Dog ID Date Observation Dog ID DateObservation 13490 Jan. 18, 2018 Loose stool 2753822 Jan. 18, 2018 Loosestool 13490 Feb. 04, 2018 Loose stool 2753822 Jan. 21, 2018 Food vomit13513 Jan. 16, 2018 Small amount loose stool 2753822 Feb. 10, 2018 Loosestool 13513 Jan. 18, 2018 Loose stool 2753822 Mar. 15, 2018 Loose stoolwith blood 13513 Jan. 19, 2018 Afraid and shaking head 2753822 Mar. 18,2018 Loose stool 13513 Jan. 25, 2018 Shaking head 2753822 Mar. 20, 2018Loose stool 13536 Jan. 14, 2018 Food and chew vomit 2753822 Mar. 24,2018 Two instances of loose stool 13536 Jan. 18, 2018 Loose stool2753822 Mar. 25, 2018 Loose stool 13536 Jan. 22, 2018 Food vomit priorto dosing 2753822 Mar. 31, 2018 Food vomit 13536 Jan. 26, 2018 Foodvomit prior to dosing 2784123 Jan. 18, 2018 Loose stool 13536 Jan. 29,2018 Bile vomit 2784123 Mar. 18, 2018 Loose stool 13536 Feb. 04, 2018Bile vomit with blood 2784123 Mar. 21, 2018 Loose stool 13536 Feb. 12,2018 Loose stool with mucus 2784123 Mar. 24, 2018 Two instances of loosestool 13536 Feb. 15, 2018 Loose stool 2784123 Mar. 29, 2018 Loose stool13536 Feb. 16, 2018 Loose stool 2808987 Jan. 18, 2018 Loose stool 13536Mar. 21, 2018 Loose stool 2803987 Feb. 05, 2018 Loose stool 13536 Mar.24, 2018 Loose stool 2808987 Feb. 10, 2018 Loose stool 13644 Jan. 18,2018 Loose stool 2803987 Mar. 20, 2018 Loose stool 13644 Feb. 02, 2018Loose stool with mucus 2963023 Jan. 18, 2018 Loose stool 13644 Feb. 04,2018 Loose stool 2963028 Feb. 10, 2018 Loose stool 13644 Feb. 05, 2018Loose stool with mucus 2963023 Mar. 20, 2018 Loose stool 13644 Feb. 06,2018 Loose stool 2963028 Mar. 22, 2018 Loose stool 13644 Feb. 07, 2018Loose stool 2963028 Mar. 24, 2018 Loose stool 13644 Feb. 10, 2018 Loosestool 2963028 Mar. 25, 2018 Loose stool 13644 Feb. 11, 2018 Loose stool13644 Feb. 15, 2018 Loose stool 13644 Mar. 15, 2018 Loose stool 13644Mar. 17, 2018 Loose stool 13644 Mar. 20, 2018 Loose stool with mucus

Conclusions

There were no adverse effects on body weights or food consumption. Groupmean alkaline phosphatase values exhibited mild elevations during thestudy without exceeding the normal reference range. The remaininghematology and serum chemistry results remained within normal limitsthroughout the study and apparent trends were not observed over time. Noclinical observations that were considered to be related to theadministration of the test article were observed for any of the dogsduring the course of the study. Overall acceptance of the treat was96.7% with 5 out of 8 consuming the treat 100% of the time for theduration of the study.

Example 13: Canine Pilot Study

A pilot study was conducted to assess the effectiveness of ElleVetMobility Oil on the treatment of osteoarthritis in canines.

Methods

Five dogs suffering from end stage osteoarthritis, joint pain, andgeriatric pain were selected for the study, as shown in Tables 21 and22.

Per manufacturer's instructions, dogs were given a loading dose of 2mg/kg every 12 hours for the first 2 weeks then reduced to 1 mg/kg every12 hours for 2 weeks. Dogs were then returned to doses of 2 mg/kg every12 hours for the final four weeks of the study.

On days 0, 14, 30, and 60, dogs were evaluated by flexion and extensionmeasurements, muscle musculature measurements, a canine brief paininventory survey, and a gait analysis using a pressure sensing walkway.

TABLE 21 Animal Information OA Body Patient Weight Score ConditionNumber Name Age Sex Breed (#) (0-3) (1-9) Medications 3496 Gipper 12 yrsFS Golden 64.9 R: 3 6 Rimadyl, apoquel, Hatch  6 mo Retriever L: 2dasuquin advanced 21652 Rocoo 15 yrs MN Mixed 67.7 B: 2 5 Keppra,Galliprant Payne  4 mo Breed 13750 Bubba 14 yrs MN Labrador 65.6 R: 2 4Galliprant, Schlimm  8 mo Retriever L: 1 Gabapentin, Theophyline 24478Aiden  7 yrs MN German 86 B: 2-3 5-5 Gabapentin, rimadyl Langhans-  2 moShepherd as needed Lindstadt 19821 Moose 11 yrs MN Mixed 65 L: 3/3 5Tramadol as needed Baker  7 mo Breed

TABLE 22 Animal history Patient Number Name Enrollment Date HistoryNotes 3496 Gipper Wed, Jun. 11, 2014 Bilateral medial shoulder syndrome(Subscapular tendinopathy); Hatch Bilateral chronic supraspinatusinsertionopathy - Bilateral shoulder arthroscopy and radio-frequencytreatment; Hobbles application, Bilateral elbow arthroscopy (2011);ADPC/PRP injections-bilateral supraspinatus, Intra-articular injectionsADPC/ACS-bilateral shoulders (2011, 2012); ADPC/PRP injection-Bilateralbiceps, Left teres (2014); ADPC/PRP injection-right shoulder, elbow,biceps (2016); PRP injection-right elbow (2016); OsteoBioScaffinjection- right elbow (2017). 21652 Rocoo Fri, Jun. 13, 2014 Elbowarthritis, history of seizure activity, history of elevated liver Payneenzymes 13750 Bubba Tue, Jun. 17, 2014 Bilateral elbow OA, hind limbweakness Schlimm 24478 Aiden Tue, Jul. 1, 2014 Bilateral Hip DysplasiaLanghans- Lindstadt 19821 Moose Fri, Jul. 18, 2014 Left medial shouldersyndrome, bilateral surpaspinatus Baker tendinopathies (R > L), L FCP ->L elbow scope & L RF tx performed (May 2016); L elbow OA

Results

Three out of five owners (60%) reported a significant improvement inpain severity score and pain interference score. Gait analysis revealedthat total pressure index (TPI %), step/stride ratio, and stancepercentage did not significantly improve or decline throughout thelength of the study, as shown in Tables 23-34 and FIGS. 5A-5F. Flexionimproved in 3 out of 5 dogs and declined by >5 degrees in 2 out of 5dogs. Extension improved in 2 out of 5 dogs and declined in 1 out of 5dogs. Following completion of the study, 3 out of 4 owners that respondto a questionnaire indicated that they would like to continue using thesupplements. Improvements observed by owners included improved functionand comfort laying down, rising, resting, walking, energy, playing, andoverall health.

TABLE 23 Total pressure index (TPI) Patient Average TPI (%) Walk AverageTPI (%) Trot Number Name Date LF RF LH RH LF RF LH RH 1 Gipper Hatch Day0 26.3 26.9 21.0 25.8 25.8 26.2 22.5 25.5 Day 14 26.5 26.4 21.9 25.224.8 26.3 24.0 25.0 Day 30 25.7 25.7 24.1 24.3 26.8 26.2 24.5 22.4 Day60 26 26.4 21.5 26 2 Rocco Payne Day 0 26.4 28.8 21.8 23 26.1 29.3 21.423.4 Day 14 27 30.3 21.3 21.5 27.4 27.8 21.1 24 Day 30 28 30.3 19.3 22.628 29.1 21.5 21.6 Day 60 27.4 28.9 21.6 21.9 25.9 28.7 21.4 24.2 3 BubbaDay 0* 31.6 31 18.7 18.6 28.8 30.9 18.7 21.5 Schlimm Day 0 30.8 31.719.2 18.2 28.8 32.5 19.9 18.9 Day 14 31.8 31.2 18.9 18 29.4 31.9 19.7 19Day 30 31.4 30.7 19.3 18.5 29.7 32 19.8 18.7 Day 60 31.4 31.3 18.5 18.831.2 33.4 17.1 18.1 4 Aiden Day 0 31 32 18.4 18.5 31.8 29.1 19.4 19.6Langhans- Day 14 32.6 30.3 18.4 18.8 31.2 31.7 18.3 18.9 Lindstadt Day30 31.9 32.2 18 18 31.4 29.1 19.3 20.2 Day 60 32.1 30.7 18.2 18.9 31.229.8 19.4 19.5 5 Moose Baker Day 0 25.1 34.4 20.9 19.5 23.3 35.6 20.820.1 Day 14 25.1 35 21.1 18.8 23.1 36.2 20.1 20.4 Day 30 24.5 35.6 19.520.4 22.1 37.2 20.3 20.3 Day 60 25.1 34.5 19.5 20.8 23.7 36.2 19.920.1 * = removed from study

TABLE 24 Exam notes Patient Number Name Date Exam Notes 1 Gipper HatchDay 0 Mild mid lumbar pain-reaction to palpation; right elbow thick/crepitus; left elbow swollen- moderate medial Day 14 Moderate left elboweffusion (medial) Day 30 Day 60 P was scuffing at a trot, cannotcurrently be processed. O does not think that he saw any effect duringthe study and actually think that P’s mood dropped while receiving thehigher dose. O also was upset that the gel capsules he received were notlarge enough to hold even a half dose. 2 Rocco Payne Day 0 Mild ->Moderate discomfort from L5 to LS; Discomfort for hip extension & iliopalpation bilaterally Day 14 bilat ilio discomfort & discomfort for hipextension L > R, significant discomfort for elbow flexion bilat, modeffusion bilat elbow medially, no back discomfort noted Day 30 Day 60 3Bubba Day 0* **P had to be removed during the Schlimm first week of thestudy due to impacted/infected anal glad. P had to go onto IV antibioticrestarted study once P was back to normal. Day 0 Bilat elbow discomfortfor flexion (L > R) Day 14 Day 30 O notes that P has been much morefeisty and playful Day 60 4 Aiden Day 0 Langhans- Day 14 Lindstadt Day30 Day 60 5 Moose Baker Day 0 Discomfort for R shoulderextension-mineralization in area of R supraspinatus tendon Day 14 Day 30Day 60 O stated that they did not see an improvement during the study.Hip radiographs were taken after the final recheck. It was discoveredthat P also has bilat HD/OA. *= removed from study

TABLE 25 Measurements - Part 1 Subjec- Humeral tive Musculature LamenessCircumference Patient Score (cm) Number Name OA Date (0-6) Left Right 1Gipper Bilateral Day 0 3 33 33 Hatch Elbows Day 14 3 34 34 Day 30 3 3232 Day 60 3 33 33 2 Rocco Bilateral Day 0 4 35 35 Payne Elbows Day 14 436.5 36 Day 30 4 36 36 Day 60 3 36 35 3 Bubba Bilateral Day 0* 3 37 37Schlimm Elbows Day 0 3 36 37 Day 14 3 36 36 Day 30 2 36 37 Day 60 2 3636 4 Aiden Bilateral Day 0 2 47 47 Langhans- Hips Day 14 2 46 47.5Lindstadt Day 30 1 47 47 Day 60 1 37 37 5 Moose Left Day 0 3 34 34.5Baker Elbow Day 14 2 33.5 34 Day 30 3 34 35.5 Day 60 3 34 35 * = removedfrom study

TABLE 26 Measurements-Part 2 Discomfort on Palpation (N-None, GoniometryMeasurements (°) Y-Yes, M-Mild) Patient Left Right Left Right NumberName OA Date Extension Flexion Extension Flexion Extension FlexionExtension Flexion 1 Gipper Bilateral Day 0 160 30 160 39 N Y N Y HatchElbows Day 14 160 35 165 40 N Y Y Y Day 30 164 38 158 42 Y Y Y Y Day 60165 41 162 44 N Y Y N 2 Rocco Bilateral Day 0 152 52 164 60 Y Y Y YPayne Elbows Day 14 162 69 164 55 N Y N Y Day 30 158 69 163 63 N Y N YDay 60 164 70 162 68 N Y N Y 3 Bubba Bilateral Day 0* 158 42 163 50 N YN Y Schlimm Elbows Day 0 165 45 162 52 N Y N Y Day 14 170 44 174 42 N YN Y Day 30 170 38 165 46 N Y N Y Day 60 161 42 168 46 N Y N Y 4 AidenBilateral Day 0 150 48 156 52 Y N Y N Langhans- Hips Day 14 140 50 14847 Y N Y N Lindstadt Day 30 149 60 145 49 Y N Y N Day 60 145 50 142 52 YN Y N 5 Moose Left Day 0 157 69 162 28 Y Y Y N Baker Elbow Day 14 160 64170 31 Y Y N N Day 30 152 60 172 28 Y Y N N Day 60 162 64 172 28 N Y YN * = removed from study

TABLE 27 Schedule Patient Number Name Day Date 1 Gipper Hatch Day 0 Tue,Jun. 12, 2018 2 Rocco Payne Day 0 Thu, Jun. 14, 2018 3 Bubba Schlimm Day0* Mon, Jun. 18, 2018 **P had to be removed during the first week of thestudy due to impacted/infected anal glad. P had to go onto IV antibioticrestarted study once P was back to normal. Day 0 Mon, Jul. 9, 2018 4Aiden Langhans- Day 0 Mon, Jul. 2, 2018 Lindstadt 5 Moose Baker Day 0Thu, Jul. 19, 2018 *= removed from study

TABLE 28 Canine brief pain index-description of pain Description ofPain: No Pain (0) → Extreme Pain (10) Pain at Pain at Pain at worst inleast in average Pain Patient last 7 last 7 in last 7 Pain rightSeverity Number Name Date days days days now Mean Comments 1 Gipper Day0 8 5 6 5 6 Hatch Day 14 8 5 7 6 7 Day 30 8 6 6 6 7 Day 60 8 6 7 6 7 2Rocco Day 0 6 6 5 6 6 Payne Day 14 9 9 9 9 9 Day 30 7 5 6 6 6 Day 60 5 34 3 4 3 Bubba Day 0* 6 4 5 5 5 **P had to be Schlimm removed during thefirst week of the study due to impacted/infected anal glad. P had to goonto IV antibiotic restarted study once P was back to normal. Day 0 5 44 4 4 Day 14 4 3 3 3 3 Day 30 5 3 4 5 4 Day 60 3 2 2 2 2 4 Aiden Day 0 95 7 9 8 Langhans- Day 14 7 4 5 3 5 Lindstadt Day 30 7 4 5 4 5 Day 60 8 34 3 5 5 Moose Day 0 7 3 6 6 6 Baker Day 14 7 4 5 5 5 Day 30 7 3 5 4 5Day 60 5 4 5 5 5

TABLE 29 Canine brief pain index-description of function Description ofFunction: Does Not Interfere (0) → Completely Interferes (10) Pain hasinterfered Pain has with interfered Quality of ability to with Life inthe Pain has Pain has rise to Pain has Pain has ability to last 7 daysinterfered interfered standing interfered interfered climb up (Poor →with with from with with (stairs, Fair → general enjoyment lying abilityto ability to curbs, Good → activity of life in down in walk in run inetc) in Pain Very Good Patient in last 7 last 7 last 7 last 7 last 7last 7 Interference → Number Name Date days days days days days daysMean Excellent) 1 Gipper Day 7 7 8 6 9 7 7 Good Hatch 0 Day 6 5 8 6 9 77 Good 14 Day 7 6 8 6 8 8 7 Good 30 Day 7 6 8 6 9 6 7 Good 60 2 RoccoDay 6 6 8 8 10 10 8 Very Good Payne 0 Day 8 8 7 7 10 10 8 Fair 14 Day 65 6 4 5 10 6 Very Good 30 Day 3 2 3 2 7 10 5 Very Good 60 3 Bubba Day 63 0 5 9 6 5 Good Schlimm 0* Day 3 3 3 5 7 5 4 Good 0 Day 3 3 3 3 7 6 4Very Good 14 Day 5 4 4 4 7 4 5 Good 30 Day 2 1 1 2 3 1 2 Very Good 60 4Aiden Day 7 8 7 8 9 8 8 Fair Langhans- 0 Lindstadt Day 4 5 5 4 4 5 5Good 14 Day 4 5 4 5 6 5 5 Good 30 Day 2 4 4 3 3 5 4 Good 60 5 Moose Day2 2 2 2 3 4 3 Very Good Baker 0 Day 5 3 4 4 6 5 5 Good 14 Day 4 2 5 4 55 4 Very Good 30 Day 4 3 6 3 5 4 4 Good 60 * = removed from study

TABLE 30 Full gait data-walks Part 1 Patient Average TPI (%) Walk StepLength Stride Length Number Name Date LF RF LH RH LF RF LH RH LF RF LHRH 1 Gipper Day 26.3 26.9 21.0 25.8 32.585 30.600 31.650 31.235 63.35063.050 62.950 62.950 Hatch 0 Day 26.5 26.4 21.9 25.2 29.596 30.05727.966 31.446 59.852 59.750 59.552 59.470 14 Day 25.7 25.7 24.1 24.330.842 30.824 30.386 31.619 61.683 61.683 62.036 61.930 30 Day 26.0 26.421.5 26.0 31.083 31.844 31.821 31.232 62.904 63.020 63.043 63.107 60 2Rocco Day 26.4 28.8 21.8 23.0 37.714 40.795 37.246 40.751 78.778 78.55378.040 78.148 Payne 0 Day 27.0 30.3 21.3 21.5 34.911 39.238 34.51439.132 74.154 74.204 73.615 73.637 14 Day 28.0 30.3 19.3 22.6 32.56737.123 34.396 34.979 69.572 69.809 69.420 69.578 30 Day 27.4 28.9 21.621.9 37.370 40.368 38.088 39.272 78.098 77.798 77.221 77.432 60 3 BubbaDay 30.8 31.7 19.2 18.2 44.450 43.688 42.005 46.344 88.530 88.159 88.63588.424 Schlimm 0 Day 31.8 31.2 18.9 18.0 41.677 42.757 40.654 43.85884.416 84.561 84.801 84.501 14 Day 31.4 30.7 19.3 18.5 40.255 41.44438.424 43.342 82.028 81.598 81.936 81.936 30 Day 31.4 31.3 18.5 18.843.487 45.702 42.958 46.337 89.517 88.918 89.235 89.535 60 4 Aiden Day31.0 32.0 18.4 18.5 57.309 56.180 58.120 56.198 113.453 113.665 114.794114.865 Langhans- 0 Lindstadt Day 32.6 30.3 18.4 18.8 49.939 48.78949.346 49.054 99.272 98.407 98.460 98.037 14 Day 31.9 32.2 18.0 18.051.946 50.571 52.106 50.747 102.376 103.434 102.729 103.152 30 Day 32.130.7 18.2 18.9 50.800 50.504 51.806 50.490 101.441 101.424 102.235102.252 60 5 Moose Day 25.1 34.4 20.9 19.5 35.285 36.647 39.741 33.66971.522 72.390 73.152 73.766 Baker 0 Day 25.1 35.0 21.1 18.8 35.65635.097 39.580 32.569 70.594 71.271 71.773 72.632 14 Day 24.5 35.6 19.520.4 35.963 36.233 39.960 32.299 72.284 72.408 72.231 72.496 30 Day 25.134.4 19.5 20.8 34.491 35.909 39.317 32.427 70.242 70.792 71.671 71.89360 = removed from study

TABLE 31 Full gait data-walks Part 2 Patient Stance % Stance TimeStride/Step Number Name Date LF RF LH RH LF RF LH RH LF RF LH RH 1Gipper Day 64.0 68.6 57.4 60.7 0.430 0.460 0.385 0.405 51.4 48.5 50.349.6 Hatch 0 Day 68.2 70.1 59.6 61.2 0.449 0.460 0.392 0.400 49.4 50.347.0 52.9 14 Day 66.9 67.9 59.7 59.9 0.458 0.463 0.408 0.410 50.0 50.049.0 51.1 30 Day 67.3 68.4 58.7 60.1 0.443 0.450 0.387 0.395 49.4 50.550.5 49.5 60 2 Rocco Day 64.8 64.3 56.1 59.5 0.534 0.525 0.458 0.49147.9 51.9 47.7 52.1 Payne 0 Day 66.2 65.8 57.6 61.2 0.573 0.568 0.4880.518 47.1 52.9 46.9 53.1 14 Day 69.3 66.4 59.0 63.5 0.682 0.653 0.5790.628 46.8 53.2 49.5 50.3 30 Day 62.3 63.1 55.2 57.2 0.447 0.453 0.3890.404 47.9 51.9 49.3 50.7 60 3 Bubba Day 60.3 61.0 57.5 57.5 0.494 0.4940.475 0.474 50.2 49.6 47.4 52.4 Schlimm 0 Day 60.4 60.2 56.4 55.0 0.4530.451 0.421 0.411 49.4 50.6 47.9 51.9 14 Day 62.6 62.6 58.9 58.4 0.5340.535 0.501 0.500 49.1 50.8 46.9 52.9 30 Day 60.1 60.8 57.0 57.1 0.4740.480 0.453 0.451 48.6 51.4 48.1 51.8 60 4 Aiden Day 53.9 53.7 48.4 48.50.330 0.331 0.297 0.296 50.5 49.4 50.6 48.9 Langhans- 0 Lindstadt Day60.6 59.9 56.6 55.2 0.446 0.445 0.417 0.410 50.3 49.6 50.1 50.0 14 Day56.6 57.9 50.9 53.0 0.379 0.391 0.342 0.352 50.7 48.9 50.7 49.2 30 Day57.7 58.5 53.6 53.2 0.413 0.421 0.387 0.385 50.1 49.8 50.7 49.4 60 5Moose Day 60.1 61.4 57.7 57.7 0.405 0.413 0.388 0.384 49.3 50.6 54.345.6 Baker 0 Day 63.2 66.9 58.0 58.1 0.429 0.455 0.393 0.394 50.5 49.255.1 44.8 14 Day 61.6 59.9 56.8 57.6 0.394 0.381 0.361 0.364 49.8 50.055.3 44.6 30 Day 61.0 66.8 57.7 57.7 0.407 0.446 0.388 0.385 49.1 50.754.9 45.1 60 = removed from study

TABLE 32 Full gait data-trots Part 1 Patient Average TPI (%) Trot StepLength Stride Length Number Name Date LF RF LH RH LF RF LH RH LF RF LHRH 1 Gipper Day 25.8 26.2 22.5 25.5 36.830 35.510 37.285 35.720 72.85072.200 73.650 72.650 Hatch 0 Day 24.8 26.3 24.0 25.0 28.776 40.27940.868 31.082 69.208 69.918 72.262 70.561 14 Day 27.4 26.9 23.0 23.637.412 37.465 36.293 39.123 74.789 75.141 75.071 75.635 30 Day — — — — —— — — — — — — 60 2 Rocco Day 26.1 29.3 21.4 23.4 41.118 45.579 40.69745.649 86.766 87.014 86.638 86.353 Payne 0 Day 27.4 27.8 21.1 24.043.480 45.385 41.875 47.308 89.041 88.759 89.676 88.970 14 Day 28.0 29.121.5 21.6 40.030 45.014 40.993 44.715 84.861 84.861 86.078 85.707 30 Day25.9 28.7 21.4 24.2 43.621 45.861 43.603 46.214 89.450 90.226 89.80390.283 60 3 Bubba Day 28.8 32.5 19.9 18.9 47.096 47.766 47.413 47.27294.474 95.391 94.827 94.827 Schlimm 0 Day 29.4 31.9 19.7 19.0 45.74147.149 45.314 47.879 92.498 93.271 93.049 92.932 14 Day 29.7 32.0 19.818.7 42.189 40.756 41.871 42.302 82.867 83.167 84.720 83.820 30 Day 31.233.4 17.1 18.1 46.270 44.549 45.286 46.210 91.034 91.264 91.352 91.95160 4 Aiden Day 31.8 29.1 19.4 19.6 65.740 65.511 65.846 64.805 130.739131.798 130.245 131.727 Langhans- 0 Lindstadt Day 31.2 31.7 18.3 18.964.682 61.817 63.465 61.860 126.824 127.035 126.048 125.042 14 Day 31.429.1 19.3 20.2 63.698 62.389 63.302 61.701 126.418 126.453 125.448125.360 30 Day 31.2 29.8 19.4 19.5 63.236 64.929 64.950 63.712 128.605127.970 128.958 128.993 60 5 Moose Day 23.3 35.6 20.8 20.1 45.942 46.84245.612 46.574 92.696 92.915 91.962 92.304 Baker 0 Day 23.1 36.2 20.120.4 46.119 48.122 44.898 48.609 94.636 94.414 94.181 93.229 14 Day 22.137.2 20.3 20.3 43.110 45.164 42.968 45.254 88.688 88.357 88.399 88.55430 Day 23.7 36.2 19.9 20.1 43.808 47.159 43.102 47.773 91.250 91.01791.006 91.027 60 = removed from study

TABLE 33 Full gait data-trots Part 2 Patient Stance % Stance TimeStep/Stride Ratio Number Name Date LF RF LH RH LF RF LH RH LF RF LH RH 1Gipper Day 60.4 62.6 51.0 53.2 0.330 0.345 0.280 0.295 50.6 49.2 50.649.2 Hatch 0 Day 55.3 61.6 55.1 51.7 0.265 0.286 0.245 0.241 41.6 57.656.6 44.1 14 Day 60.0 61.4 49.4 50.4 0.334 0.341 0.276 0.282 50.0 49.948.3 51.7 30 Day — — — — — — — — — — — — 60 2 Rocco Day 58.3 57.5 47.850.1 0.371 0.370 0.306 0.319 47.4 52.4 47.0 52.9 Payne 0 Day 55.8 55.843.3 45.3 0.350 0.352 0.279 0.284 48.8 51.1 46.7 53.2 14 Day 59.4 57.447.9 50.0 0.382 0.376 0.314 0.332 47.2 53.0 47.6 52.2 30 Day 53.3 52.341.7 44.2 0.301 0.296 0.243 0.255 48.8 50.8 48.6 51.2 60 3 Bubba Day50.5 49.4 44.0 43.3 0.295 0.286 0.269 0.261 49.9 50.1 50.0 49.9 Schlimm0 Day 50.9 50.4 42.3 42.1 0.290 0.285 0.245 0.243 49.5 50.6 48.7 51.5 14Day 53.6 55.1 48.5 50.1 0.337 0.350 0.315 0.327 50.9 49.0 49.4 50.5 30Day 53.7 54.9 49.9 48.3 0.333 0.341 0.314 0.302 50.8 48.8 49.6 50.3 60 4Aiden Day 45.0 44.0 40.1 39.0 0.241 0.235 0.215 0.208 50.3 49.7 50.649.2 Langhans- 0 Lindstadt Day 44.5 43.8 38.5 38.5 0.228 0.226 0.1990.199 51.0 48.7 50.3 49.5 14 Day 46.4 46.0 39.0 38.8 0.259 0.255 0.2130.210 50.4 49.3 50.5 49.2 30 Day 44.4 45.1 37.7 38.1 0.241 0.249 0.2030.207 49.2 50.7 50.4 49.4 60 5 Moose Day 44.7 48.2 42.9 42.5 0.214 0.2320.205 0.203 49.6 50.4 49.6 50.5 Baker 0 Day 43.5 47.8 43.3 42.9 0.2030.221 0.203 0.197 48.7 51.0 47.7 52.1 14 Day 47.5 50.5 44.7 45.5 0.2280.245 0.215 0.220 48.6 51.1 48.6 51.1 30 Day 46.3 49.8 42.7 45.2 0.2230.243 0.204 0.217 48.0 51.8 47.4 52.5 60 = removed from study

TABLE 34 Gait analysis summary Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 Walk WalkWalk Walk Walk Step/Stride- Step/Stride- Step/Stride- Step/Stride-Step/Stride- declined Day 14, improves day 30 & Declined day 60Unchanged Unchanged improved day 60 60 Stance %- Stance %- Stance %-Stance %- Siance %- Improved day 14, declined day 30, unchanged slightlydeclined decline day 14, 60 30, and 60 improved day 60 day 14, 30 TrotTrot Trot Trot Trot Step/Stride- Step/Stride- Step/Stride- Step/Stride-Step/Stride- declined day 14 slowly improved at Unchanged (slightlyUnchanged slightly declined at (no day 60 data) each recheck declined)each recheck Stance %- Stance %- Stanee %6- Stiinee %- Stttfice %-Declined day 14, declined day 30 slightly declined day slightly improvedforelimbs slight slightly improved 30. 60 day 14, 30, 60 improve day 30but day 30 (no day 60 hindlimb declined, data) declined day 60

Example 14: Feline Safety Study

A 12-week safety study was performed in felines to evaluate the safetyof an oil containing CBD.

Animals and Study Design

Eight cats, 2-6 years old, weighing 3.33-5.17 kg at study start wereselected for the study, as shown in Table 35.

TABLE 35 Animal information Cat ID Sex Date of Birth 15EGA5 FS Apr. 8,2015 13IRD3 FS Oct. 5, 2013 15KGA2 FS Apr. 7, 2015 13CNL3 MC Sep. 20,2013 13CCL1 MC Feb. 11, 2013 GJY3 MC Jul 17, 2011 15KGC3 MC Apr. 8, 201513CPJ7 FS Oct. 25, 2013Cats were single housed in cages of a size in accordance with the AnimalWelfare Act, with a 12-hour-light/12-hour-dark cycle and targetedconditions of 50° to 85° F. Cages, food bowls, water bowls and litterboxes were cleaned daily and sanitized in accordance with the AnimalWelfare Act. Fresh tap water, fit for human consumption, was availablead libitum by means of stainless steel bowls. There were no knowncontaminants that were reasonably expected to be present in the dietarymaterial that were known to be capable of interfering with the purposeor conduct of the study

During the study, the control diet, Purina Cat Chow, was the sole sourceof food supplied to each animal once daily for approximately 4 hours.Cats were fed according to ideal body condition and were fasted for aminimum of 12 hours prior to blood collections. CBD oil was orallyadministered twice a day using a 1 ml syringe at a dosage of 2 mg/kg.The total dose per 24 hour period was 4 mg/kg. Dosing is shown in Tables36 and 37.

TABLE 36 Dosage per week (mL) (weeks 1-6) Week Cat ID Sex 1 2 3 4 5 615EGA5 FS 0.14 0.14 0.14 0.14 0.14 0.14 13IRD3 FS 0.13 0.14 0.14 0.140.14 0.14 15KGA2 FS 0.13 0.14 0.14 0.14 0.14 0.14 13CNL3 MC 0.19 0.190.19 0.19 0.19 0.19 13CCL1 MC 0.20 0.20 0.20 0.20 0.21 0.20 GJY3 MC 0.210.22 0.22 0.22 0.23 0.23 15KGC3 MC 0.19 0.20 0.21 0.21 0.21 0.21 13CPJ7FS 0.15 0.15 0.15 0.15 0.16 0.16

TABLE 37 Dosage per week (mL) (weeks 7-12) Week Cat ID Sex 7 8 9 10 1112 15EGA5 FS 0.14 0.14 0.14 0.14 0.14 0.13 13IRD3 FS 0.14 0.14 0.14 0.140.13 0.13 15KGA2 FS 0.14 0.14 0.14 0.14 0.14 0.13 13CNL3 MC 0.19 0.190.19 0.19 0.19 0.19 13CCL1 MC 0.21 0.20 0.20 0.20 0.19 0.19 GJY3 MC 0.230.23 0.23 0.23 0.23 0.22 15KGC3 MC 0.21 0.21 0.21 0.21 0.21 0.21 13CPJ7FS 0.16 0.15 0.15 0.15 0.15 0.15

CBC and Serum Chemistry

Prior to study initiation, 5 milliliters of blood was collected for eachcat and was used to determine eligibility for the study. During thestudy, 5 milliliters of blood was collected weekly (±2 days). Blood wascollected via jugular venipuncture in sterile syringes. Samples weresplit into two tubes: a red-top serum separator tube and a lavender-topEDTA tube. Redtop tubes were spun in a refrigerated centrifuge for 15minutes at 3000 RPM after being allowed to clot. Lavender-top tubes wereplaced on a rocker to allow the blood to adequately mix with theanticoagulant. Blood samples were packaged and sent bypriority-overnight to Antech Diagnostics for analysis.

Pharmacokinetic (PK) Blood Collection

On the first day of dosing, blood was collected for a PK analysis from 6of the 8 cats. The most cooperative cats were selected for the PKanalysis. Approximately 4 milliliters of blood was collected via jugularvenipuncture in sterile syringes at one day prior to treatment(timepoint 0) and then 1, 4, 8 and 24 hours after treatment. Sampleswere placed into a red top clotting tube with no serum separator. Serumwas harvested by centrifuging the tubes at 3000 RPM for 15 minutes. Theharvested serum was placed in cyrovials stored at −70° C. Each tube waslabeled with the cat id, date of collection and collection time point.Samples were shipped overnight on dry ice to the Proteomics &Metabolomics Facility at Colorado State University.

Clinical Observations

A veterinarian performed a complete physical examination to all catsprior to the initiation of the study and at study completion. Each catwas evaluated as to general health, body and hair coat condition.Qualified personnel performed clinical observations twice daily inaccordance with Summit Ridge Farms' Program of Veterinary Care and SOPVC-003 (Rounds Observations). All animals were evaluated twice dailywith reference to SOP VC-016 (Recognizing Pain, Stress and/or Distress).Clinical laboratory diagnostic procedures were performed as needed.Veterinary care was given as appropriate to each individual animal inaccordance with the Program of Veterinary Care.

Blood Analysis

Blood was analyzed for white blood cell count, red blood cell count,hemoglobin, hematocrit, MCV, MCHC, MCH, and platelet count along with acomplete differential. In addition, a 22-test chemistry screen wasperformed consisting of Glucose, Urea Nitrogen, Creatinine, TotalProtein, Albumin, Total Bilirubin, Alkaline Phosphatase, ALT, AST, CPK,Cholesterol, Calcium, Phosphorus, Sodium, Potassium, Chloride, A/GRatio, BUN/Creatinine Ratio, Globulin, Triglycerides, GGTP andMagnesium. Measurements were taken prior to the start of the study andthen weekly during the course of the study.

PK Analysis Extraction of Cannabidiol from Feline serum for LC-MS

Aliquots of feline serum were delivered to the facility on dry ice andstored at −80° C. upon receipt. For cannabidiol (CBD) extraction, serumwas thawed on ice and 50 μL of each sample was placed into a 2.0 mlglass extraction vial (VWR ROBO Unassembled Autosampler Vial) kept onchilled on ice. 200 μL of cold (−20C) 100% Acetonitrile (spiked with 60ng/mL of d3-CBD) was added to each sample and vortexed at roomtemperature for 5 minutes. 200 μL of water was added and vortexed for anadditional 5 minutes. 1 ml of 100% hexane was then added to each sampleand vortexed for a final 5 minutes. Phase separation was enhanced undercentrifugation at 3000 rpm for 15 minutes at 4C. The upper hexane layerwas transferred to new-labeled glass vials (˜900 uL per sample),carefully avoiding the middle and lower layers. Samples wereconcentrated to dryness under N₂ and resuspended in 60 μL of 100%acetonitrile.

Standard Curve

An 8 point standard curve of CBD was generated in matrix backgroundusing a blank serum. Concentrations ranged from 0 ng/mL 1000 ng/mL(3.2×dilution series). 50 uL of each spiked serum sample was extractedas above.

LC-MS/MS Analysis

LC-MS/MS was performed on a Waters Acquity M-Class UPLC coupled to aWaters Xevo TQ-S triple quadrupole mass spectrometer. Chromatographicseparations were carried out on a Waters BEH C18 iKey Separation Device(150 μm×50 mm, 1.7 μM). Mobile phases were 99.9% acetonitrile, 0.1%formic acid (B) and water with 0.1% formic acid (A). The analyticalgradient was as follows: time=0 min, 70% B; time=1.0 min, 70% B; time=6min, 100% B; time 7.0 min, 100% B; time 7.5 min, 70% B. Total run timewas 10 minutes. Flow rate was 3.0 μL/min and injection volume was 2.0μL. Samples were held at 6° C. in the autosampler, and the column wasoperated at 70° C. The MS was operated in selected reaction monitoring(SRM) mode, where a parent ion is selected by the first quadrupole,fragmented in the collision cell, then a fragment ion selected for bythe third quadrupole. Product ions, collision energies, and conevoltages were optimized for each analyte by direct injection ofindividual synthetic standards. Inter-channel delay was set to 3 ms. TheMS was operated in positive ionization mode with the capillary voltageset to 3.6 kV. Source temperature was 120° C. and desolvationtemperature 992° C. Desolvation gas flow was 1 L/hr, cone gas flow was150 L/hr, and collision gas flow was 0.2 mL/min. Nebulizer pressure(nitrogen) was set to 7 Bar. Argon was used as the collision gas.

Data Analysis and Statistics

All Raw data files were imported into the Skyline open source softwarepackage. Each target analyte was visually inspected for retention timeand peak area integration. Peak areas were extracted for targetcompounds detected in biological samples and normalized to the peak areaof the appropriate internal standard in each sample using in-house RScript (TQS-tools). CBD concentrations were calculated in nanograms permilliliter of extract (0.06 mL) and then back calculated to nanogramsper mL of serum (0.05 mL of serum).

Calculation of Variance using QC Pool

50 uL of all serum samples (feline and canine) were pooled into a singleQuality Control sample and 50 uL was extracted as described above. TheQC pool was injected every 10 samples and CBD concentrations were usedto measure the technical variance over the course of data acquisition.

Limits of Detection (LOD) and Limits of Quantification (LOQ)

The LOD and LOQ represent the lower limits of detection andquantification for each compound in the matrix of this study. LOD arecalculated based on the standard deviation of the response (Sy) of the 0point calibration standard (i.e. 0 ng/mL CBD as an estimate on noise)and the slope of the calibration curve (S) at levels approximating theLOD according to the formula: LOD=3*(Sy/S). LOQ=10*(Sy/S). The Sy of yis the standard deviation used for LOD and LOQ calculation.

Results Body Weight

The mean average weight change for cats during the 12 weeks of the studywas 0.06 kg (1.04%). Weight data is presented in Tables 38 and 39.

TABLE 38 Weekly body weights (weeks 1-6) Week Cat ID Sex Base 1 2 3 4 56 15EGA5 FS 3.43 3.60 3.62 3.76 3.62 3.60 3.62 13IRD3 FS 3.34 3.48 3.613.61 3.48 3.51 3.52 15KGA2 FS 3.33 3.42 3.48 3.51 3.53 3.53 3.49 13CNL3MC 4.66 4.63 4.70 4.81 4.82 4.81 4.78 13CCL1 MC 5.03 5.01 5.00 5.11 5.145.07 5.19 GJY3 MC 5.17 5.53 5.55 5.57 5.63 5.64 5.67 15KGC3 MC 4.82 5.115.21 5.18 5.27 5.26 5.31 13CPJ7 FS 3.72 3.73 3.86 3.87 3.93 3.92 3.92Mean: 4.19 4.31 4.38 4.43 4.43 4.42 4.44 SD: 0.806 0.849 0.828 0.8240.880 0.871 0.898

TABLE 39 Weekly body weights (weeks 7-12) Week Cat ID Sex 7 8 9 10 11 12Chg. % Chg. 15EGA5 FS 3.50 3.51 3.49 3.38 3.37 3.33 −0.10 −2.92 13IRD3FS 3.46 3.42 3.38 3.36 3.27 3.25 −0.09 −2.69 15KGA2 FS 3.43 3.43 3.403.39 3.34 3.37 0.04 1.20 13CNL3 MC 4.78 4.82 4.82 4.84 4.80 4.83 0.173.65 13CCL1 MC 4.99 4.96 4.96 4.87 4.85 4.74 −0.29 −5.77 GJY3 MC 5.675.67 5.69 5.71 5.55 5.50 0.33 6.38 15KGC3 MC 5.35 5.33 5.29 5.21 5.155.11 0.29 6.02 13CPJ7 FS 3.87 3.86 3.82 3.81 3.80 3.81 0.09 2.42 Mean:4.38 4.38 4.36 4.32 4.37 4.24 0.06 1.04 SD: 0.920 0.922 0.936 0.9430.920 0.902 0.210 4.439

Food Consumption

The mean daily food consumption per week for cats during the study was62 g. Food consumption data is presented in Tables 40 and 41.

TABLE 40 Average daily food consumption per week (weeks 1-6) Week Cat IDSex 1 2 3 4 5 6 15EGA5 FS 70 70 65 56 55 55 13IRD3 FS 70 70 60 51 50 5015KGA2 FS 70 70 65 61 55 50 13CNL3 MC 62 59 65 65 64 64 13CCL1 MC 75 7087 54 64 69 GJY3 MC 100 100 95 86 80 75 15KGC3 MC 100 98 92 93 89 8213CPJ7 FS 70 70 68 66 60 55 Mean: 77 76 75 67 64 63 SD: 14.6 14.8 14.215.3 13.3 12.0

TABLE 41 Average daily food consumption per week (weeks 6-12) Week CatID Sex 7 8 9 10 11 12 Average 15EGA5 FS 51 50 50 50 50 50 56 13IRD3 FS46 45 45 45 45 45 52 15KGA2 FS 50 50 50 50 50 50 56 13CNL3 MC 64 65 6264 61 61 63 13CCL1 MC 63 54 75 61 42 54 64 GJY3 MC 71 66 65 55 45 45 7415KGC3 MC 76 66 64 60 60 60 78 13CPJ7 FS 51 50 50 50 49 50 57 Mean: 5956 58 54 50 52 62 SD: 11.2 8.5 10.3 6.7 6.8 6.2 9.3

Test Article Acceptance

Overall all cats exhibited behaviors of licking, salivating, pacing,head shaking, chomping, dose resentment (uncooperative behavior), etc.at various intervals throughout the study that were indicative ofdislike of the test article. Results are shown in Tables 42-69.

TABLE 42 Observations following test article administration (days 1-3)Day 1 Day 2 Day 3 Cat Id AM PM AM PM AM PM 15EGA5 chomping, whitelicking licking licking licking, licking foamy mouth chomping 13IRD3chomping, licking, head head shake, chomping licking, head shakesalivating shake, drooling licking chomping 15KGA2 chomping, lickinglicking licking licking, licking salivating chomping 13CNL3 lickinglicking, head head shake, — head shake, head shake shake, foaminglicking licking 13CCL1 chomping, head licking, licking chomping,chomping, — shake, salivating chomping salivating salivating GJY3chomping licking, head shake, licking licking head shake chompinglicking 15KGC3 chomping licking licking licking head shake, lickinggrimace 13CPJ7 chomping, pacing, licking, licking, pacing pacing pacingchomping, pacing pacing licking — denotes no reaction recorded

TABLE 43 Observations following test article administration (days 4-6)Day 4 Day 5 Day 6 Cat Id AM PM AM PM AM PM 15EGA5 drooling lickinglicking head shake head shake — 13IRD3 — chomping — — licking chewing15KGA2 very relaxed chomping — licking licking — 13CNL3 pacing — — — —little head shake 13CCL1 head shake chomping — chomping chomping — GJY3licking licking licking — licking licking 15KGC3 — licking chompinglicking — — 13CPJ7 pacing pacing pacing pacing pacing pacing — denotesno reaction recorded

TABLE 44 Observations following test article administration (days 7-9)Day 7 Day 8 Day 9 Cat Id AM PM AM PM AM PM 15EGA5 head shake head shakehead shake head shake licking licking 13IRD3 — — — head shake — 15KGA2 —chewing — licking chomping — 13CNL3 — — — head shake — — 13CCL1 headshake head shake licking — — chomping GJY3 licking licking — — — licking15KGC3 licking licking/head shake licking — head shake — 13CPJ7 pacingpacing pacing pacing pacing pacing — denotes no reaction recorded

TABLE 45 Observations following test article administration (days 10-12)Day 10 Day 11 Day 12 Cat Id AM PM AM PM AM PM 15EGA5 — licking — headshake chomping licking 13IRD3 — — — — — — 15KGA2 — — — head shakelicking — 13CNL3 licking licking — licking — — 13CCL1 — — head shake —head shake head shake GJY3 — — — licking — — 15KGC3 head shake licking —— licking licking 13CPJ7 pacing pacing pacing pacing pacing pacing —denotes no reaction recorded

TABLE 46 Observations following test article administration (days 13-15)Day 13 Day 14 Day 15 Cat Id AM PM AM PM AM PM 15EGA5 — — head shakelicking chomping licking 13IRD3 licking — — — — — 15KGA2 licking lickingchomping — chomping licking 13CNL3 — — — chomping — — 13CCL1 — — foodvomit — — — before dosing GJY3 licking — hairball vomit licking — —before dosing 15KGC3 licking head shake — — — licking 13CPJ7 pacingpacing pacing — pacing pacing — denotes no reaction recorded

TABLE 47 Observations following test article administration (days 16-18)Day 16 Day 17 Day 18 Cat Id AM PM AM PM AM PM 15EGA5 chomping, — headshake licking licking licking licking 13IRD3 — — licking — salivatingbefore — dosing 15KGA2 licking — head shake, — — — licking 13CNL3 — — —licking hairball vomit — before dosing 13CCL1 — — — — — — GJY3 lickinglicking — — — licking 15KGC3 — — head shake head shake head shake —13CPJ7 pacing pacing chomping pacing — pacing — denotes no reactionrecorded

TABLE 48 Observations following test article administration (days 19-21)Day 19 Day 20 Day 21 Cat Id AM PM AM PM AM PM 15EGA5 — — head shakelicking head shake head shake 13IRD3 — — — — — — 15KGA2 — chompingchomping chomping licking licking 13CNL3 — — — — licking — 13CCL1 — — —— — — GJY3 — licking licking — licking licking 15KGC3 head shake headshake licking head shake head shake head shake 13CPJ7 — pacing headshake pacing pacing pacing — denotes no reaction recorded

TABLE 49 Observations following test article administration (days 22-24)Day 22 Day 23 Day 24 Cat Id AM PM AM PM AM PM 15EGA5 licking — licking —licking head shake 13IRD3 — — — — — — 15KGA2 — licking head shake — headshake licking 13CNL3 — — head shake head shake head shake — 13CCL1licking, head shake — — chomping — uncooperative, licking GJY3 — headshake licking licking — — 15KGC3 head shake head shake licking — licking— 13CPJ7 pacing pacing head shake — pacing pacing — denotes no reactionrecorded

TABLE 50 Observations following test article administration (days 25-27)Day 25 Day 26 Day 27 Cat Id AM PM AM PM AM PM 15EGA5 licking — licking —head shake licking 13IRD3 — — head shake licking — head shake 15KGA2licking licking — licking — licking 13CNL3 licking licking licking —licking — 13CCL1 head shake head shake — chomping head shake — GJY3 — —licking licking licking, head shake licking 15KGC3 — — head shake,licking head shake licking head shake, licking 13CPJ7 pacing pacingpacing pacing pacing pacing — denotes no reaction recorded

TABLE 51 Observations following test article administration (days 28-30)Day 28 Day 29 Day 30 Cat Id AM PM AM PM AM PM 15EGA5 licking — — —licking, licking 13IRD3 — — — head shake — head shake 15KGA2 — headshake — licking — licking 13CNL3 — — head shake head shake licking —13CCL1 licking head shake, licking licking — — — GJY3 licking — lickinglicking, — licking 15KGC3 — licking, head shake head shake, lickinglicking licking head shake 13CPJ7 pacing pacing pacing pacing headshake, pacing pacing — denotes no reaction recorded

TABLE 52 Observations following test article administration (days 31-33)Day 31 Day 32 Day 33 Cat Id AM PM AM PM AM PM 15EGA5 head shake lickinghead shake head shake head shake licking 13IRD3 head shake — — licking —head shake 15KGA2 — — chomping, licking — chomping licking 13CNL3licking head shake licking licking — — 13CCL1 — licking — — — head shakeGJY3 licking licking — licking licking — 15KGC3 licking, chomping headshake head shake head shake, licking — head shake 13CPJ7 head shakepacing head shake pacing pacing pacing — denotes no reaction recorded

TABLE 53 Observations following test article administration (days 34-36)Day 34 Day 35 Day 36 Cat Id AM PM AM PM AM PM 15EGA5 licking lickinglicking — — chomping 13IRD3 — — head shake — — — 15KGA2 chomping,licking licking — chomping chomping, licking — 13CNL3 — — — — head shake— 13CCL1 — — licking licking — — GJY3 — licking — licking — — 15KGC3licking licking — licking — licking 13CPJ7 pacing pacing pacing lickingpacing pacing — denotes no reaction recorded

TABLE 54 Observations following test article administration (days 37-39)Day 37 Day 38 Day 39 Cat Id AM PM AM PM AM PM 15EGA5 chomping head shakelicking licking licking head shake, licking 13IRD3 — — head shake — — —15KGA2 licking licking — licking, head shake — licking 13CNL3uncooperative head shake jumping, licking — jumping, licking licking13CCL1 uncooperative — — drooling, head shake — head shake, licking GJY3— licking — — — jumping 15KGC3 uncooperative licking head shake, lickinghead shake head shake, licking head shake, licking 13CPJ7 pacing pacingpacing pacing pacing pacing — denotes no reaction recorded

TABLE 55 Observations following test article administration (days 40-42)Day 40 Day 41 Day 42 Cat Id AM PM AM PM AM PM 15EGA5 head shake, licking, licking — licking — — 13IRD3 — — licking drooling licking — 15KGA2chomping licking — — — head shake 13CNL3 — — jumping, head shake headshake licking jumping, licking 13CCL1 — — head shake — head shake,jumping gagging GJY3 — — head shake licking licking licking 15KGC3 headshake, licking head shake, licking head shake, licking licking — headshake, licking 13CPJ7 pacing pacing pacing pacing pacing pacing, headshake — denotes no reaction recorded

TABLE 56 Observations following test article administration (days 43-45)Day 43 Day 44 Day 45 Cat Id AM PM AM PM AM PM 15EGA5 chomping, lickingchomping, licking head shake, licking licking chewing chewing 13IRD3 — —— — — — 15KGA2 head shake, licking head shake licking head shake,chomping head shake, chewing — 13CNL3 — — — — head shake head shake13CCL1 — gagging food vomit — head shake head shake before dosing GJY3licking licking — — licking a little chewing 15KGC3 head shake, lickinglicking head shake, licking head shake licking head shake chomping13CPJ7 pacing pacing pacing pacing pacing pacing — denotes no reactionrecorded

TABLE 57 Observations following test article administration (days 46-48)Day 46 Day 47 Day 48 Cat Id AM PM AM PM AM PM 15EGA5 licking, chomping —licking, head shake licking licking head shake, licking 13IRD3 — — — — —drooling 15KGA2 licking licking head shake, chomping chomping chewing,head shake licking 13CNL3 — — licking — licking — 13CCL1 head shakelicking, chewing — — head shake — GJY3 licking head shake — licking —licking 15KGC3 head shake, licking — head shake — licking licking 13CPJ7pacing, head shake pacing pacing pacing head shake, pacing pacing —denotes no reaction recorded

TABLE 58 Observations following test article administration (days 49-51)Day 49 Day 50 Day 51 Cat Id AM PM AM PM AM PM 15EGA5 licking lickinglicking, head shake licking, head shake head shake, chomping licking13IRD3 — — — — head shake — 15KGA2 licking licking licking — head shakelicking 13CNL3 licking head shake — head shake — licking 13CCL1 lickinghead shake salavating — — gagging GJY3 head shake licking head shake —licking head shake, licking 15KGC3 licking, head shake head shake,licking licking, head shake licking, head shake head shake, chompinglicking 13CPJ7 head shake, pacing licking, head shake head shake pacingpacing pacing — denotes no reaction recorded

TABLE 59 Observations following test article administration (days 52-54)Das 52 Day 53 Day 54 Cat Id AM PM AM PM AM PM 15EGA5 licking — chompinglicking head shake, licking — 13IRD3 — head shake — head shake — —15KGA2 — licking head shake, chomping licking head shake, licking headshake, licking 13CNL3 head shake — — — — — 13CCL1 licking — gagging,chomping — head shake gagging, head shake GJY3 licking licking — — — —15KGC3 head shake, licking head shake chomping head shake, lickingchomping, head shake head shake, licking 13CPJ7 head shake, pacingpacing pacing pacing pacing — denotes no reaction recorded

TABLE 60 Observations following test article administration (days 55-57)Das 55 Day 56 Day 57 Cat Id AM PM AM PM AM PM 15EGA5 chomping, droolinglicking chomping, licking licking head shake, chomping, chomping,licking drooling 13IRD3 head shake — — head shake — — 15KGA2 chomping —chomping head shake, licking — licking 13CNL3 — — — — — — 13CCL1 gagginggagging — head shake — gagging GJY3 — licking — licking licking licking15KGC3 head shake, chomping head shake head shake, chomping head shake,chomping licking chomping, licking 13CPJ7 pacing pacing pacing pacinglicking pacing — denotes no reaction recorded

TABLE 61 Observations following test article administration (days 58-60)Das 58 Day 59 Day 60 Cat Id AM PM AM PM AM PM 15EGA5 licking — headshake — — licking 13IRD3 — — — licking — — 15KGA2 licking — licking —licking licking 13CNL3 — head shake head shake licking head shake headshake 13CCL1 gagging licking — head shake, licking licking licking GJY3licking licking licking head shake licking, head shake licking 15KGC3head shake, chomping head shake, licking head shake violent head shakelicking head shake 13CPJ7 pacing pacing pacing pacing, licking pacing,head shake pacing — denotes no reaction recorded

TABLE 62 Observations following test article administration (days 61-63)Das 61 Day 62 Day 63 Cat Id AM PM AM PM AM PM 15EGA5 — — lickingchomping, licking head shake licking 13IRD3 head shake licking headshake licking head shake — 15KGA2 — head shake head shake, lickinglicking, head shake head shake, licking head shake, licking 13CNL3licking — — — — head shake 13CCL1 gagging head shake — gagging gagginggagging GJY3 — — licking head shake — — 15KGC3 head shake, licking headshake chomping, licking — head shake, licking head shake, licking 13CPJ7pacing uncooperative, pacing pacing pacing pacing pacing — denotes noreaction recorded

TABLE 63 Observations following test article administration (days 64-66)Das 64 Day 65 Day 66 Cat Id AM PM AM PM AM PM 15EGA5 head shake, lickinglicking licking licking, head shake chomping head shake, licking 13IRD3head shake — licking — — — 15KGA2 pacing, licking pacing head shake headshake, licking head shake head shake, licking 13CNL3 — — licking — —head shake, licking 13CCL1 head shake, licking licking — gagging licking— GJY3 licking licking, head shake — licking licking licking 15KGC3 headshake, licking licking head shake, licking — head shake, licking headshake 13CPJ7 pacing pacing pacing pacing pacing, head shake pacing —denotes no reaction recorded

TABLE 64 Observations following test article administration (days 67-69)Das 67 Day 68 Day 69 Cat Id AM PM AM PM AM PM 15EGA5 — licking headshake, licking licking licking head shake, licking 13IRD3 head shake —head shake head shake head shake — 15KGA2 licking — head shake licking —licking 13CNL3 head shake — — — licking — 13CCL1 — — gagging gagginghead shake, licking head shake GJY3 licking licking licking licking,head shake licking licking 15KGC3 head shake head shake, licking headshake, chomping head shake, licking head shake head shake 13CPJ7 pacingpacing, licking pacing pacing pacing pacing — denotes no reactionrecorded

TABLE 65 Observations following test article administration (days 70-72)Das 70 Day 71 Day 72 Cat Id AM PM AM PM AM PM 15EGA5 licking head shakelicking head shake, licking head shake, licking licking 13IRD3 — — headshake head shake — — 15KGA2 licking — chomping, licking licking headshake, licking — 13CNL3 licking, head shake head shake, licking lickinglicking ha — 13CCL1 head shake licking gagging gagging head shakegagging, drooling GJY3 licking licking licking licking, head shakelicking head shake, licking 15KGC3 licking head shake head shake,licking head shake, licking head shake, licking — 13CPJ7 pacing pacingpacing pacing pacing pacing — denotes no reaction recorded

TABLE 66 Observations following test article administration (days 73-75)Das 73 Day 74 Day 75 Cat Id AM PM AM PM AM PM 15EGA5 — head shakechomping, licking, licking licking, head shake head shake head shake13IRD3 — — head shake head shake head shake — 15KGA2 — licking licking —head shake, pacing head shake, licking 13CNL3 licking head shake — —head shake, licking — 13CCL1 gagging gagging, licking head shake,licking gagging, drooling — — GJY3 licking licking licking — lickinglicking 15KGC3 licking, chewing licking, head shake head shake, lickinghead shake, licking chomping head shake, licking 13CPJ7 pacing, headshake pacing, head shake pacing pacing pacing pacing — denotes noreaction recorded

TABLE 67 Observations following test article administration (days 76-78)Das 76 Day 77 Day 78 Cat Id AM PM AM PM AM PM 15EGA5 licking, chompinghead shake, licking chomping, licking, — head shake licking 13IRD3 —head shake — — — — 15KGA2 licking head shake, licking licking head shake— licking 13CNL3 head shake — licking head shake head shake licking,head shake 13CCL1 gagging, licking gagging head shake gagging, headshake gagging licking GJY3 licking licking licking licking licking —15KGC3 head shake, licking head shake, chomping licking, head shakelicking head shake, licking licking 13CPJ7 head shake, pacing pacinghead shake pacing pacing head shake, pacing — denotes no reactionrecorded

TABLE 68 Observations following test article administration (days 79-81)Das 79 Day 80 Day 81 Cat Id AM PM AM PM AM PM 15EGA5 licking, head shakelicking head shake, licking — head shake, licking licking 13IRD3 headshake head shake — head shake licking head shake, licking 15KGA2 licking— — head shake, licking licking licking, head shake 13CNL3 head shakelicking licking licking licking — 13CCL1 licking gagging, grimace —gagging licking drooling GJY3 licking licking head shake, lickinglicking licking licking 15KGC3 head shake head shake, licking headshake, licking head shake head shake head shake, licking 13CPJ7 pacinghead shake, pacing pacing, licking pacing, head shake pacing, head shakepacing — denotes no reaction recorded

TABLE 69 Observations following test article administration (days 82-84)Das 82 Day 83 Day 84 Cat Id AM PM AM PM AM PM 15EGA5 licking, head shakelicking licking licking licking licking 13IRD3 — head shake head shake —— — 15KGA2 head shake licking — — — licking 13CNL3 licking head shakelicking head shake head shake head shake 13CCL1 gagging head shake,licking licking licking, head shake grimace, head shake licking, grimaceGJY3 licking licking licking, grimace licking, head shake lickinglicking 15KGC3 licking, head shake licking head shake licking headshake, licking head shake, licking 13CPJ7 pacing licking head shakelicking, pacing head shake, pacing head shake, licking — denotes noreaction recorded

Hematology and Serum Chemistry

Beginning in Week 2, there was an increase in the mean alanineaminotransferase (ALT) value for the group. This value remainedincreased from baseline until the end of the study. Mild increases inindividual ALT levels were observed in the majority of the catsthroughout the study. The cat with the greatest increase in ALT (abovethe normal reference range of 100 U/L), with a concurrent increase inaspartate aminotransferase (AST), was 13CNL3. Beginning in Week 4, thiscat's ALT and AST levels began to decrease, but remained elevated frombaseline. ALT levels remained above the normal reference range, shown inTable 70, for the duration of the study. Also during Week 2, the ALTlevels of cats 131RD3 and 13CPJ7 increased by 23 to 31 U/L,respectively, from baseline values. The ALT levels of cat 13CPJ7returned to baseline by Week 10. At Week 4, the ALT of cat 13CCL1 waselevated from baseline by 32 U/L. Levels returned to baseline by Week10. The test article appeared to cause mild ALT changes in the majorityof cats with one cat maintaining elevated ALT levels above normal limitsthroughout the study. The group mean values of all other bloodparameters remained within normal limits and no apparent trends werenoted. Hematology and serum chemistry results are presented in Tables71-74.

TABLE 70 Hematology and serum chemistry normal reference rangesParameter Normal Reference Ranges Total Protein (g/dL): 5.2-8.8 g/dLAlbumin (g/dL): 2.5-3.9 g/dL Globutin (g/dL): 2.5-5.3 g/dL A/G Ratio:0.4-1.5 Ratio AST (IU/L): 10-100 IU/L ALT (IU/L): 10-100 IU/L AlkalinePhosphatase (IU/L): 6-102 IU/L GGTP (IU/L): 1-10 IU/L Total Bilirubin(mg/dL): 0.1-0.4 mg/dL Urea Natogen (mg/dL): 14-36 mg/dL Creatinine(mg/dL): 0.6-2.4 mg/dL BUN/Creatinine Ratio: 4-33 Ratio Phophorus(mg/dL): 2.4-8.2 mg/dL Glucose (mg/dL): 64-170 mg/dL Calcium (mg/dL):8.2-10.8 mg/dL Magnesium (mEq/L): 1.5-2.5 mEq/L Sodium (mEq/L): 145-158mEq/L Potassium (mEq/L): 3.4-5.6 mEq/L Chloride (meEq/L): 104-128 mEq/LCholesteral (mg/dL): 75-220 mg/dL Triglycerides (mg/dL): 25-160 mg/dLCPK (IU/L): 56-529 IU/L WBC(10

/μL): 3.5-16.0 10

/μL RBC(10

/μL): 5.9-9.9 10

/μL Hemoglobin (g/dL): 9.3-15.9 g/dL Hematocrit (%): 29-48% MCV (fL):37-61 fL MCH (pg): 11-21 pg MCHC (g/dL): 30-38 g/dL Platelets (10

/μL): 200-500 10

/μL Absolue Polys (μL): 2500-8500 μL Absolute Bands (μL): 0 μL AbsoluteLymphs (μL): 1200-8000 μL Absolute Monos (μL): 0-600 μL Absolute Eos(μL): 0-1000 μL Absolute Basos (μL): 0-150 μL

indicates data missing or illegible when filed

TABLE 71 Summary of hematology and serum chemistry results-Part 1 TotalAlkaline Total Urea Protein Albumin Globulin A/G AST ALT PhosphataseGGTP Bilirubin Nitrogen Creatinine (g/dL) (g/dL) (g/dL) Ratio (U/L)(U/L) (U/L) (U/L) (mg/dL) (mg/dL) (mg/dL) Initial Results Mean: 7.2 3.24.0 0.8 21 51 30 2 0.1 23 1.3 SD: 0.46 0.27 0.60 0.18 4.8 15.2 15.4 0.80.00 2.6 0.19 N: 8 8 8 8 8 8 8 8 8 8 8 Week 2 Mean: 7.1 3.2 3.9 0.9 27104 33 2 0.1 23 1.1 SD: 0.51 0.30 0.70 0.20 19.5 117.7 16.7 1.0 0.04 3.10.18 N: 8 8 8 8 8 8 8 8 8 8 8 Week 4 Mean: 6.7 3.2 3.5 0.9 24 90 30 10.1 22 1.2 SD: 0.48 0.30 0.67 0.21 11.6 85.2 16.1 0.0 0.00 2.9 0.13 N: 88 8 8 8 8 8 8 8 8 8 Week 6 Mean: 6.5 9.3 3.2 1.1 25 80 32 1 0.1 30 1.1SD: 0.41 0.31 0.63 0.26 13.1 48.1 17.0 0.4 0.04 3.5 0.11 N: 8 8 8 8 8 88 8 8 8 8 Week 8 Mean: 7.1 3.4 3.8 0.9 25 76 29 2 0.2 20 1.3 SD: 0.490.36 0.63 0.19 10.8 46.8 15.3 0.9 0.00 2.4 0.16 N: 8 8 8 8 8 8 8 8 8 8 8Week 10 Mean: 7.0 3.3 3.8 0.9 24 67 30 1 0.1 23 1.3 SD: 0.48 0.31 0.610.20 7.7 30.2 18.6 0.4 0.00 2.7 0.11 N: 8 8 8 8 8 8 8 8 8 8 8 FinalResults Mean: 7.1 3.2 3.9 0.9 24 78 28 1 0.1 19 1.3 SD: 0.55 0.31 0.730.20 9.4 42.2 15.9 0.4 0.00 1.6 0.30 N: 8 8 8 8 8 8 8 8 8 8 8

TABLE 72 Summary of hematology and serum chemistry results-Part 2 BUN/Creatinine Phosphorus Glucose Calcium Magnesium Sodium PotassiumChloride Cholesterol Triglycerides Ratio (mg/dL) (mg/dL) (mg/dL) (mEq/L)(mEq/L) (mEq/L) (mEq/L) (mEq/L) (mg/dL) Initial Results Mean: 18 4.5 909.6 1.9 151 4.7 119 139 32 SD: 3.3 1.08 7.2 0.41 0.16 2.3 0.66 2.8 24.24.4 N: 8 8 8 8 8 8 8 8 8 8 Week 2 Mean: 22 4.9 84 9.4 2.0 153 5.2 122126 37 SD: 2.5 1.10 11.0 0.31 0.12 1.6 0.48 1.9 13.5 12.5 N: 8 8 8 8 8 88 8 8 8 Week 4 Mean: 19 4.6 85 9.0 1.8 153 4.7 121 123 28 SD: 2.7 0.976.9 0.37 0.10 1.6 0.41 1.8 17.6 3.0 N: 8 8 8 8 8 8 8 8 8 8 Week 6 Mean:18 4.8 79 9.3 1.9 153 5.2 121 125 29 SD: 2.4 0.96 6.4 0.35 0.15 1.5 0.281.3 17.1 7.3 N: 8 8 8 8 8 8 8 8 8 8 Week 8 Mean: 16 4.3 87 9.5 1.8 1544.7 122 128 26 SD: 1.4 0.92 8.3 0.02 0.11 3.4 0.77 2.4 15.6 4.2 N: 8 8 88 8 8 8 8 8 8 Week 10 Mean: 17 4.1 85 9.2 1.8 152 4.5 120 123 22 SD: 1.50.90 6.4 0.30 0.10 1.7 0.43 1.6 19.5 3.9 N: 8 8 8 8 8 8 8 8 8 8 FinalResults Mean: 15 4.1 86 9.3 1.8 132 4.5 120 123 25 SD: 2.0 0.64 10.20.31 0.13 1.5 0.30 1.5 19.4 4.5 N: 8 8 8 8 8 8 8 8 8 8

TABLE 73 Summary of hematology and serum chemistry results-Part 3 I CPKWBC RBC Hemoglobin Hematocrit MCV MCH MCHC Platelets (U/L)(10{circumflex over ( )}3/mm3) (10{circumflex over ( )}6/mm3) (g/dL) (%)(um{circumflex over ( )}3) (uug) (g/dl) (10{circumflex over ( )}3/mm3)Initial Results Mean: 197 14.0 8.8 11.4 39 44 13.0 30 308 SD: 89.3 4.450.73 1.09 4.1 2.5 0.35 2.1 138.2 N: 8 8 8 8 8 8 8 8 8 Week 2 Mean: 15312.1 8.3 11.1 36 44 13.4 31 375 SD: 88.2 3.01 0.77 0.95 3.0 3.1 0.42 1.6106.2 N: 8 8 8 8 8 8 8 8 8 Week 4 Mean: 114 13.6 8.0 10.7 34 42 13.4 32374 SD: 40.7 4.10 0.96 1.31 3.9 1.0 0.32 0.5 84.8 N: 8 8 8 8 8 8 8 8 8Week 6 Mean: 133 12.3 8.8 11.7 39 44 13.3 30 362 SD: 66.2 4.14 0.79 0.973.4 1.8 0.80 1.4 99.6 N: 8 8 8 8 8 8 8 8 8 Week 8 Mean: 106 12.9 9.012.4 40 44 13.7 31 361 SD: 32.4 3.75 0.73 1.06 3.7 1.7 0.46 1.0 57.9 N:8 8 8 8 8 8 8 8 8 Week 10 Mean: 137 10.9 8.8 11.6 40 45 13.3 29 329 SD:76.9 3.82 0.89 1.43 4.5 1.9 0.43 1.2 63.7 N: 8 8 8 8 8 8 8 8 8 FinalResults Mean: 126 12.5 9.0 11.8 39 43 13.3 31 289 SD: 40.0 4.56 1.111.46 5.6 2.6 0.64 1.4 54.5 N: 8 8 8 8 8 8 8 8 8

TABLE 74 Summary of hematology and serum chemistry results-Part 4 Abs %Abs % Abs % Abs % Abs % Abs % Polys Polys Bands Bands Lymphs LymphsMonos Monos Eos Eos Basos Basos Initial Results Mean: 7980 56 0 0 448132 428 3 1149 0 0 0 SD: 3059.8 9.0 0.0 0.0 1466.5 7.0 138.0 1.0 417.83.4 0.0 0.0 N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 2 Mean: 7762 64 0 0 2988 26495 4 817 7 0 0 SD: 2917.9 7.0 0.0 0.0 902.2 7.0 255.7 1.4 392.0 2.1 0.00.0 N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 4 Mean: 8993 65 0 0 3315 25 417 3876 7 0 0 SD: 3181.2 4.0 0.0 0.0 781.7 5.3 187.0 0.8 395.3 2.7 0.0 0.0N: 8 8 8 8 8 8 8 8 8 8 8 8 Week 6 Mean: 7032 57 0 0 4264 35 440 3 539 50 0 SD: 2708.4 7.4 0.0 0.0 1366.9 3.6 296.7 1.2 530.6 5.3 0.0 0.0 N: 8 88 8 8 8 8 8 8 8 8 8 Week 8 Mean: 7394 56 0 0 3856 31 545 4 1026 8 30 0SD: 3061.4 7.0 0.0 0.0 802.9 8.3 288.9 2.1 601.2 3.2 54.9 0.5 N: 8 8 8 88 8 8 8 8 8 8 8 Week 10 Mean: 6159 57 0 0 3732 34 355 4 605 5 0 0 SD:2300.3 7.2 0.0 0.0 1484.7 8.1 108.3 1.1 451.0 2.2 0.0 0.0 N: 8 8 8 8 8 88 8 8 8 8 8 Final Results Mean: 7847 61 0 0 3614 31 364 3 630 0 0 0 SD:3819.8 9.8 0.0 0.0 1051.9 9.3 207.7 0.7 258.2 2.9 0.0 0.0 N: 8 8 8 8 8 88 8 8 8 8 8

Clinical Observations

During the study, occasional instances of loose stool and emesis wererecorded, as shown in Table 75. Cat ID #13CCL1 was observed having fiveinstances of food emesis. Cat ID #13CNL3 was observed having oneinstance of hairball emesis and one instance of hair and bile emesis.Cat ID #131RD3 was observed having one instance of food emesis. Cat ID#15EGA5 was observed having three instances of food vomit and oneinstance of hair and bile emesis. Cat ID #GJY3 was observed having twoinstances of hairball emesis and one instance of food emesis. Occasionalepisodes of hairball and food emesis are not unusual in the cat colonyand were not considered to be related to the test article.

TABLE 75 Clinical observations Cat Id Date Observation 13CCL1 Jan. 19,2018 Very cals, relaxed pros to dosing in am and pm 13CCL1 Jan. 21, 2018Very calm, relaxed prior to dosing is pm 13CCL1 Jan. 25, 2018 Food vomit13CCL1 Jan. 31, 2018 Food vomit 13CCL1 Feb. 9, 2018 Food vomit 13CCL1Mar. 2, 2018 Food vomit 13CCL1 Apr. 8, 2018 Food vomit 13CNL3 Jan. 19,2018 Very calm, relaxed pries to dosing is am and pm 13CNL3 Jan. 21,2018 Very calm, relaxed pros to dosing is pm 13CNL3 Jan. 22, 2018 Veryrelaxed 13CNL3 Feb. 4, 2018 Hairball vomit 13CNL3 Apr. 6, 2018 Bilevomit and hairball vomit 13IRD3 Feb. 8, 2018 Semi digested food vomit15EGA5 Jan. 26, 2018 Food vomit 15EGA5 Feb. 8, 2018 Semi digested foodvomit 15EGA5 Mar. 9, 2018 Bile vomit and hairball vomit 15EGA5 Mar. 19,2018 Digested food vomit 15KGA2 Jan. 19, 2018 Very calm, relaxed priorto dosing in am and pm 15KGA2 Jan. 21, 2018 Very calm, relaxed prior todosing in am and pm 15KGA2 Jan. 22, 2018 Very relaxed 15KGC3 Jan. 19,2018 Very calm, relaxed prior to dosing in pm GJY3 Jan. 31, 2018Hairball vomit GJY3 Feb. 18, 2018 Digested food vomit GJY3 Mar. 19, 2018Hairball vomit

PK Data

Table 76 shows the quantification of cannabidiol in feline serum andTable 77 shows cat cannabadiol pharmacokinetics.

TABLE 76 Cannabidiol quantification in feline serum. PMF Replicate ppbin No. Animal ID Species Time Point (A or B) Serum 53 13CCL1 Feline  1day prior A ND 53  1 day prior B ND 59 60 min B  32.85  59 60 min A 34.26  65  4 hr B  1.69** 65  4 hr A  1.82** 71  8 hr B  65.42  71  8hr A  79.30  77 24 hr B  42.76  77 24 hr A  44.88  52 13CNL3 Feline  1day prior A ND 52  1 day prior B ND 58 60 min B  24.44  58 60 min A 26.32  64  4 hr A ND 64  4 hr B ND 70  8 hr B  1.82** 70  8 hr A 2.22*  76 24 hr A 141.92  76 24 hr B 147.74  50 13IRD3 Feline  1 dayprior A ND 50  1 day prior B ND 56 60 min B  44.14  56 60 min A  45.40 62  4 hr B  1.53** 62  4 hr A ND 68  8 hr A ND 68  8 hr B ND 74 24 hr A 10.28  74 24 hr B  10.31  49 15EGA5 Feline  1 day prior A ND 49  1 dayprior B ND 55 60 min B  28.10  55 60 min A  31.02  61  4 hr A ND 61  4hr B ND 67  8 hr A  44.23  67  8 hr B  46.05  73 24 hr A  13.95  73 24hr B  17.17  51 15KGA2 Feline  1 day prior A ND 51  1 day prior B ND 5760 min A ND 57 60 min B ND 63  4 hr A ND 63  4 hr B ND 69  8 hr B365.18  69  8 hr A 376.28  75 24 hr B  0.18** 75 24 hr A  0.36** 54 GJY3Feline  1 day prior A ND 54  1 day prior B ND 60 60 min A 378.59  60 60min B 535.08  66  4 hr A  51.48  66  4 hr B  68.31  72  8 hr A  71.64 72  8 hr B  79.59  78 24 hr B  33.12  78 24 hr A  35.88  Cannabidiolquantification in Feline Serum is reported as ng/mL (ppb). ND = NotDetected (no quantifiable value). *= values below calculated Limit ofQuantification (6.2 ppb). **= values below calculated Limit of Detection(1.9 ppb).

TABLE 77 Cat cannabadiol pharmacokinetics Cat # Cmax Tmax T½ el AUC 0->tMRT 15EGA5 75.3 1 1.2 212.2 2.1 13IRD3 40.5 1 1.3 125.0 2.4 15KGA2 53.31 1.7 194.1 2.9 13CNL3 21.2 4 1.7 134.2 5.4 13CCL1 20.4 1 1.7 60.2 2.7GJY3 47.6 4 1.2 265.0 5.7 15KGC3 8.8 1 2.3 54.2 3.8 13CPJ7 12.1 1. 2.342.4 2.4 Oral administration of 2/mg/kg cannabidiol is capsule form Cmax= Maximum concentration (ng/ml) Tmax = Time of maximum concentration(hr) T½ el = Half-life of elimination (hr) AUC 0-t = Area under thecurve (0 time to time of last collection [24 hr]) (ng-hr/ml) MRT = Meanresidence time (hr)

The LOD for CBD in feline serum was calculated to be 1.9 ng/mL (ppb inserum). The LOQ for CBD in feline serum was calculated to be 6.2 ng/mL(ppb in serum).

Conclusions

There were no adverse effects on body weights or food consumption. Groupmean alanine aminotransferase values exhibited elevations during thestudy that peaked at Week 2. Levels decreased during the followingweeks, but did not return to baseline levels. ALT levels of

one cat (13CNL3) remained significantly elevated throughout the study,exceeding normal reference ranges for the duration of the treatmentperiod. The remaining group mean hematology and serum chemistry valuesremained within normal reference limits throughout the study andapparent trends were not observed over time. No adverse clinicalobservations that were considered to be related to the administration ofthe test article were observed for any of the cats during the course ofthe study. However, acceptance of the test article was considered to bepoor.

The disclosed subject matter is not to be limited in scope by thespecific embodiments and examples described herein. Indeed, variousmodifications of the disclosure in addition to those described willbecome apparent to those skilled in the art from the foregoingdescription and accompanying figures. Such modifications are intended tofall within the scope of the appended claims.

All references (e.g., publications or patents or patent applications)cited herein are incorporated herein by reference in their entirety andfor all purposes to the same extent as if each individual reference(e.g., publication or patent or patent application) was specifically andindividually indicated to be incorporated by reference in its entiretyfor all purposes. Other embodiments are within the following claims.

1. A pharmaceutical composition comprising hemp extract and a carrier,wherein the hemp extract comprises: cannabidiol; and cannabidiolic acid;wherein the ratio of cannabidiol to cannabidiolic acid is about 0.6:1 toabout 1:0.6.
 2. The pharmaceutical composition of claim 1, where in hempextract further comprises: cannabigerolic acid; D9-tetrahydrocannabinol;and cannabichromene.
 3. The pharmaceutical composition of claim 1,wherein the hemp extract further comprises four or more of thefollowing: α-pinene; β-myrcene; β-pinene; δ-limonene; linalool;β-caryophyllene; α-humulene; nerolidol 2; guaiol; caryophyllene oxide;and α-bisabolol. 4-17. (canceled)
 18. The pharmaceutical composition ofclaim 1, wherein the composition is formulated in a carrier.
 19. Thepharmaceutical composition of claim 18, wherein the carrier is selectedfrom the group consisting of linseed oil, olive oil, fish oil, salmonoil, coconut oil, catnip oil, sesame oil, and grapeseed oil.
 20. Thepharmaceutical composition of claim 19, wherein the carrier is grapeseedoil.
 21. The pharmaceutical composition of claim 19, wherein the carrieris catnip oil. 22-27. (canceled)
 28. The pharmaceutical composition ofclaim 1, wherein the composition is formulated as a chew for oraladministration. 29-32. (canceled)
 33. A pharmaceutical compositioncomprising hemp extract and a carrier, wherein the hemp extractcomprises four or more of: α-pinene; β-myrcene; β-pinene; δ-limonene;linalool; β-caryophyllene; α-humulene; nerolidol 2; guaiol;caryophyllene oxide; and α-bisabolol. 34-46. (canceled)
 47. Thepharmaceutical composition of claim 33 wherein the pharmaceuticalcomposition is formulated as a chew for oral administration. 48-73.(canceled)
 74. A dosage form comprising the pharmaceutical compositionof claim 1 and one or more pharmaceutically acceptable additives,flavoring agents, surfactants, and adjuvants. 75-113. (canceled)
 114. Adosage form comprising: glucosamine HCl; chondroitin sulfate (76%) orhyaluronic acid; brewer's yeast; arabic gum; guar gum; a flavoringagent; hemp extract; glycerin; sunflower lecithin; and water. 115-119.(canceled)
 120. A dosage form comprising: hemp extract; peanut butter;rice bran; glucosamine HCl; sweet potato; dry molasses; sorbic acidbrewer's yeast; sugar; water; glycerin; potato starch; dehydrated peanutbutter; rice starch; and guar gum. 121-131. (canceled)
 132. A method fortreating or reducing pain in a veterinary subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of the pharmaceutical composition of claim
 1. 133-150. (canceled)151. A method for treating or reducing pain associated with arthritis,post-operative pain, acute pain, dental pain, pain associated withgingivitis, or multi joint pain in a veterinary subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of hemp extract. 152-165. (canceled)
 166. A method of achievingan area under the curve from 0 time to 24 hours of between 42.4 and 3048ng hr/ml for cannabidiol in a veterinary subject comprisingadministering to the subject an effective amount of hemp extract. 167.(canceled)
 168. The pharmaceutical composition of claim 1, wherein thehemp extract does not comprise terpenes.
 169. A dosage form comprisingthe pharmaceutical composition of claim 33 and one or morepharmaceutically acceptable additives, flavoring agents, surfactants,and adjuvants.
 170. A method for treating or reducing pain in aveterinary subject in need thereof, comprising administering to thesubject a therapeutically effective amount of the pharmaceuticalcomposition of claim
 33. 171. A method for treating or reducing pain ina veterinary subject in need thereof, comprising administering to thesubject a therapeutically effective amount of the dosage form of claim74.
 172. A method for treating or reducing pain in a veterinary subjectin need thereof, comprising administering to the subject atherapeutically effective amount of the dosage form of claim
 114. 173. Amethod for treating or reducing pain in a veterinary subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of the dosage form of claim
 117. 174. A method fortreating or reducing pain in a veterinary subject in need thereof,comprising administering to the subject a therapeutically effectiveamount of the dosage form of claim 120.